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17 pages, 1994 KiB

Open AccessArticle

An Intravenous Pharmacokinetic Study of Cannabidiol Solutions in Piglets through the Application of a Validated Ultra-High-Pressure Liquid Chromatography Coupled to Tandem Mass Spectrometry Method for the Simultaneous Quantification of CBD and Its Carboxylated Metabolite in Plasma

by Nathan Koch, Olivier Jennotte, Anna Lechanteur, Marine Deville, Corinne Charlier, Jean-Michel Cardot, Patrice Chiap and Brigitte Evrard

Pharmaceutics 2024, 16(1), 140; https://doi.org/10.3390/pharmaceutics16010140 - 20 Jan 2024

Cited by 1 | Viewed by 1437

Abstract

Cannabidiol (CBD) has multiple therapeutic benefits that need to be maximized by optimizing its bioavailability. Numerous formulations are therefore being developed and their pharmacokinetics need to be studied, requiring analytical methods and data from intravenous administration. As CBD is susceptible to hepatic metabolism, [...] Read more.

Cannabidiol (CBD) has multiple therapeutic benefits that need to be maximized by optimizing its bioavailability. Numerous formulations are therefore being developed and their pharmacokinetics need to be studied, requiring analytical methods and data from intravenous administration. As CBD is susceptible to hepatic metabolism, the requirement of any method is to quantify metabolites such as 7-COOH-CBD. We demonstrated that CBD and 7-COOH-CBD could be simultaneously and correctly quantified in piglet plasma by using an UHPLC–MS/MS technique. The validated method allowed for an accurate bioanalysis of an intravenously injected solution consisting of CBD-HPβCD complexes. The experimental pharmacokinetic profile of CBD showed multi-exponential decay characterized by a fast apparent distribution half-life (0.25 h) and an elimination half-life of two hours. The profile of 7-COOH-CBD was not linked with the first-pass metabolism, since 80% of the maximum metabolite concentration was reached at the first sampling time point, without any decrease during the period of study. A two-compartment model was optimal to describe the experimental CBD profile. This model allowed us to calculate macro–micro constants and volumes of distribution (V_ss = 3260.35 ± 2286.66 mL) and clearance (1514.5 ± 261.16 mL·h⁻¹), showing that CBD is rapidly distributed to peripheral tissues once injected and slowly released into the bloodstream. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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19 pages, 3086 KiB

Open AccessArticle

Comprehensive Physiologically Based Pharmacokinetic Model to Assess Drug–Drug Interactions of Phenytoin

by Leyanis Rodriguez-Vera, Xuefen Yin, Mohammed Almoslem, Karolin Romahn, Brian Cicali, Viera Lukacova, Rodrigo Cristofoletti and Stephan Schmidt

Pharmaceutics 2023, 15(10), 2486; https://doi.org/10.3390/pharmaceutics15102486 - 18 Oct 2023

Cited by 3 | Viewed by 3125

Abstract

Regulatory agencies worldwide expect that clinical pharmacokinetic drug–drug interactions (DDIs) between an investigational new drug and other drugs should be conducted during drug development as part of an adequate assessment of the drug’s safety and efficacy. However, it is neither time nor cost [...] Read more.

Regulatory agencies worldwide expect that clinical pharmacokinetic drug–drug interactions (DDIs) between an investigational new drug and other drugs should be conducted during drug development as part of an adequate assessment of the drug’s safety and efficacy. However, it is neither time nor cost efficient to test all possible DDI scenarios clinically. Phenytoin is classified by the Food and Drug Administration as a strong clinical index inducer of CYP3A4, and a moderate sensitive substrate of CYP2C9. A physiologically based pharmacokinetic (PBPK) platform model was developed using GastroPlus^® to assess DDIs with phenytoin acting as the victim (CYP2C9, CYP2C19) or perpetrator (CYP3A4). Pharmacokinetic data were obtained from 15 different studies in healthy subjects. The PBPK model of phenytoin explains the contribution of CYP2C9 and CYP2C19 to the formation of 5-(4′-hydroxyphenyl)-5-phenylhydantoin. Furthermore, it accurately recapitulated phenytoin exposure after single and multiple intravenous and oral doses/formulations ranging from 248 to 900 mg, the dose-dependent nonlinearity and the magnitude of the effect of food on phenytoin pharmacokinetics. Once developed and verified, the model was used to characterize and predict phenytoin DDIs with fluconazole, omeprazole and itraconazole, i.e., simulated/observed DDI AUC ratio ranging from 0.89 to 1.25. This study supports the utility of the PBPK approach in informing drug development. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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13 pages, 2268 KiB

Open AccessArticle

Effects of Hyperlipidemia on the Pharmacokinetics of Tofacitinib, a JAK 1/3 Inhibitor, in Rats

by Jong Mun Won, Hyeon Gyeom Choi, So Yeon Park, Jang-Hee Kim and So Hee Kim

Pharmaceutics 2023, 15(9), 2195; https://doi.org/10.3390/pharmaceutics15092195 - 24 Aug 2023

Cited by 2 | Viewed by 1426

Abstract

Tofacitinib, an inhibitor of Janus kinases (JAKs) 1 and 3, has been shown to be effective in the treatment of rheumatoid arthritis. The incidence of hyperlipidemia has been found to be higher in patients with rheumatoid arthritis. The present study therefore investigated the [...] Read more.

Tofacitinib, an inhibitor of Janus kinases (JAKs) 1 and 3, has been shown to be effective in the treatment of rheumatoid arthritis. The incidence of hyperlipidemia has been found to be higher in patients with rheumatoid arthritis. The present study therefore investigated the pharmacokinetics of tofacitinib after its intravenous (10 mg/kg) or oral (20 mg/kg) administration in poloxamer-407-induced hyperlipidemic (PHL) rats. The area under the plasma concentration-time curve from zero to infinity (AUC_0–∞) after intravenous administration of tofacitinib was 73.5% higher in PHL than in control rats, owing to slower time-averaged nonrenal clearance (CL_NR) in the former. Evaluation of in vitro metabolism showed that the intrinsic clearance (CL_int) of tofacitinib was 38.6% lower in PHL than in control rats, owing to the decreased protein expression of hepatic cytochrome P450 (CYP) 3A1/2 and CYP2C11 in PHL rats. Similar results were observed in PHL rats after oral administration of tofacitinib. These results were likely due to the decreased CL_NR, CL_int, and P-glycoprotein (P-gp) expression in the intestines of PHL compared to control rats. Overall, these findings indicated that hyperlipidemia slowed the metabolism of tofacitinib, increasing its plasma concentrations, and that this reduced metabolism was due to alterations in expression of the proteins CYP3A1/2, CYP2C11, and P-gp in the liver and/or intestines of PHL rats. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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16 pages, 2172 KiB

Open AccessArticle

Investigation of N-Acetyltransferase 2-Mediated Drug Interactions of Amifampridine: In Vitro and In Vivo Evidence of Drug Interactions with Acetaminophen

by Yeo-Dim Park, Yoon-Jee Chae and Han-Joo Maeng

Pharmaceutics 2023, 15(5), 1471; https://doi.org/10.3390/pharmaceutics15051471 - 11 May 2023

Viewed by 2192

Abstract

Amifampridine is a drug used for the treatment of Lambert–Eaton myasthenic syndrome (LEMS) and was approved by the Food and Drug Administration (FDA) of the United States (US) in 2018. It is mainly metabolized by N-acetyltransferase 2 (NAT2); however, investigations of NAT2-mediated [...] Read more.

Amifampridine is a drug used for the treatment of Lambert–Eaton myasthenic syndrome (LEMS) and was approved by the Food and Drug Administration (FDA) of the United States (US) in 2018. It is mainly metabolized by N-acetyltransferase 2 (NAT2); however, investigations of NAT2-mediated drug interactions with amifampridine have rarely been reported. In this study, we investigated the effects of acetaminophen, a NAT2 inhibitor, on the pharmacokinetics of amifampridine using in vitro and in vivo systems. Acetaminophen strongly inhibits the formation of 3-N-acetylamifmapridine from amifampridine in the rat liver S9 fraction in a mixed inhibitory manner. When rats were pretreated with acetaminophen (100 mg/kg), the systemic exposure to amifampridine significantly increased and the ratio of the area under the plasma concentration–time curve for 3-N-acetylamifampridine to amifampridine (AUC_m/AUC_p) decreased, likely due to the inhibition of NAT2 by acetaminophen. The urinary excretion and the amount of amifampridine distributed to the tissues also increased after acetaminophen administration, whereas the renal clearance and tissue partition coefficient (K_p) values in most tissues remained unchanged. Collectively, co-administration of acetaminophen with amifampridine may lead to relevant drug interactions; thus, care should be taken during co-administration. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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14 pages, 3079 KiB

Open AccessArticle

Potent and Selective Inhibition of CYP1A2 Enzyme by Obtusifolin and Its Chemopreventive Effects

by Eun-Ji Park, Keunwan Park, Prasannavenkatesh Durai, Ki-Young Kim, So-Young Park, Jaeyoung Kwon, Hee Ju Lee, Cheol-Ho Pan and Kwang-Hyeon Liu

Pharmaceutics 2022, 14(12), 2683; https://doi.org/10.3390/pharmaceutics14122683 - 1 Dec 2022

Cited by 2 | Viewed by 2042

Abstract

Obtusifolin, a major anthraquinone component present in the seeds of Cassia tora, exhibits several biological activities, including the amelioration of memory impairment, prevention of breast cancer metastasis, and reduction of cartilage damage in osteoarthritis. We aimed to evaluate the inhibitory effects of [...] Read more.

Obtusifolin, a major anthraquinone component present in the seeds of Cassia tora, exhibits several biological activities, including the amelioration of memory impairment, prevention of breast cancer metastasis, and reduction of cartilage damage in osteoarthritis. We aimed to evaluate the inhibitory effects of obtusifolin and its analogs on CYP1A enzymes, which are responsible for activating procarcinogens, and investigate its inhibitory mechanism and chemopreventive effects. P450-selective substrates were incubated with human liver microsomes (HLMs) or recombinant CYP1A1 and CYP1A2 in the presence of obtusifolin and its four analogs. After incubation, the samples were analyzed using liquid chromatography-tandem mass spectrometry. Molecular docking simulations were performed using the crystal structure of CYP1A2 to identify the critical interactions between anthraquinones and human CYP1A2. Obtusifolin potently and selectively inhibited CYP1A2-mediated phenacetin O-deethylation (POD) with a K_i value of 0.031 µM in a competitive inhibitory manner in HLMs, whereas it exhibited negligible inhibitory effect against other P450s (IC₅₀ > 28.6 µM). Obtusifolin also inhibited CYP1A1- and CYP1A2-mediated POD and ethoxyresorufin O-deethylation with IC₅₀ values of <0.57 µM when using recombinant enzymes. Our molecular docking models suggested that the high CYP1A2 inhibitory activity of obtusifolin may be attributed to the combination of hydrophobic interactions and hydrogen bonding. This is the first report of selective and potent inhibitory effects of obtusifolin against CYP1A, indicating their potential chemopreventive effects. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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13 pages, 2399 KiB

Open AccessArticle

Negligible Effect of Quercetin in the Pharmacokinetics of Sulfasalazine in Rats and Beagles: Metabolic Inactivation of the Interaction Potential of Quercetin with BCRP

by Ju-Hee Oh, Dokeun Kim, Haejun Lee, Gyeonghee Kim, Taehoon Park, Min Chang Kim and Young-Joo Lee

Pharmaceutics 2021, 13(12), 1989; https://doi.org/10.3390/pharmaceutics13121989 - 23 Nov 2021

Cited by 3 | Viewed by 3104

Abstract

Breast cancer resistance protein (BCRP) mediates pharmacokinetic drug interactions. This study evaluated the potential of quercetin to inhibit and induce BCRP in vitro and in vivo. The inhibition of BCRP was investigated for quercetin and its metabolites using BCRP/mBcrp1-overexpressing MDCKII cells by flow [...] Read more.

Breast cancer resistance protein (BCRP) mediates pharmacokinetic drug interactions. This study evaluated the potential of quercetin to inhibit and induce BCRP in vitro and in vivo. The inhibition of BCRP was investigated for quercetin and its metabolites using BCRP/mBcrp1-overexpressing MDCKII cells by flow cytometry. The induction of BCRP was investigated in LS174T cells using quantitative PCR. The expression of rat BCRP in rat small intestine, liver, and kidney was also measured after multiple administrations of quercetin in rats (50, 100, and 250 mg/kg, seven days). The in vivo pharmacokinetic changes of sulfasalazine following single or multiple administration of quercetin in rats and beagles were investigated. Although the induction effect of quercetin on BCRP was observed in vitro, the in vivo expression of rat BCRP was not changed by multiple quercetin administrations. Oral administration of quercetin did not affect the plasma concentration or pharmacokinetic parameters of sulfasalazine, regardless of dose and dosing period in either rats or beagles. In addition, the inhibitory effect of quercetin metabolites on BCRP/mBcrp1 was not observed. These results suggest that the in vivo drug interaction caused by quercetin via BCRP was negligible, and it may be related to the metabolic inactivation of quercetin for the inhibition of BCRP. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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18 pages, 3624 KiB

Open AccessArticle

The Selective NMDA Receptor GluN2B Subunit Antagonist CP-101,606 with Antidepressant Properties Modulates Cytochrome P450 Expression in the Liver

by Ewa Bromek, Anna Haduch, Marta Rysz, Joanna Jastrzębska, Renata Pukło, Olga Wójcikowska, Przemysław Jan Danek and Władysława Anna Daniel

Pharmaceutics 2021, 13(10), 1643; https://doi.org/10.3390/pharmaceutics13101643 - 9 Oct 2021

Cited by 3 | Viewed by 2362

Abstract

Recent research indicates that selective NMDA receptor GluN2B subunit antagonists may become useful for the treatment of major depressive disorders. We aimed to examine in parallel the effect of the selective NMDA receptor GluN2B subunit antagonist CP-101,606 on the pituitary/serum hormone levels and [...] Read more.

Recent research indicates that selective NMDA receptor GluN2B subunit antagonists may become useful for the treatment of major depressive disorders. We aimed to examine in parallel the effect of the selective NMDA receptor GluN2B subunit antagonist CP-101,606 on the pituitary/serum hormone levels and on the regulation of cytochrome P450 in rat liver. CP-101,606 (20 mg/kg ip. for 5 days) decreased the activity of CYP1A, CYP2A, CYP2B, CYP2C11 and CYP3A, but not that of CYP2C6. The alterations in enzymatic activity were accompanied by changes in the CYP protein and mRNA levels. In parallel, a decrease in the pituitary growth hormone-releasing hormone, and in serum growth hormone and corticosterone (but not T₃ and T₄) concentration was observed. After a 3-week administration period of CP-101,606 less changes were found. A decrease in the CYP3A enzyme activity and protein level was still maintained, though no change in the mRNA level was found. A slight decrease in the serum concentration of corticosterone was also maintained, while GH level returned to the control value. The obtained results imply engagement of the glutamatergic system in the neuroendocrine regulation of cytochrome P450 and potential involvement of drugs acting on NMDA receptors in metabolic drug–drug interactions. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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23 pages, 2671 KiB

Open AccessArticle

Effect of Lactic Acid Bacteria on the Pharmacokinetics and Metabolism of Ginsenosides in Mice

by Ji-Hyeon Jeon, Jaehyeok Lee, Jin-Hyang Park, Chul-Haeng Lee, Min-Koo Choi and Im-Sook Song

Pharmaceutics 2021, 13(9), 1496; https://doi.org/10.3390/pharmaceutics13091496 - 17 Sep 2021

Cited by 17 | Viewed by 3312

Abstract

This study aims to investigate the effect of lactic acid bacteria (LAB) on in vitro and in vivo metabolism and the pharmacokinetics of ginsenosides in mice. When the in vitro fermentation test of RGE with LAB was carried out, protopanaxadiol (PPD) and protopanaxadiol [...] Read more.

This study aims to investigate the effect of lactic acid bacteria (LAB) on in vitro and in vivo metabolism and the pharmacokinetics of ginsenosides in mice. When the in vitro fermentation test of RGE with LAB was carried out, protopanaxadiol (PPD) and protopanaxadiol (PPD), which are final metabolites of ginsenosides but not contained in RGE, were greatly increased. Compound K (CK), ginsenoside Rh1 (GRh1), and GRg3 also increased by about 30%. Other ginsenosides with a sugar number of more than 2 showed a gradual decrease by fermentation with LAB for 7 days, suggesting the involvement of LAB in the deglycosylation of ginsenosides. Incubation of single ginsenoside with LAB produced GRg3, CK, and PPD with the highest formation rate and GRd, GRh2, and GF with the lower rate among PPD-type ginsenosides. Among PPT-type ginsenosides, GRh1 and PPT had the highest formation rate. The amoxicillin pretreatment (20 mg/kg/day, twice a day for 3 days) resulted in a significant decrease in the fecal recovery of CK, PPD, and PPT through the blockade of deglycosylation of ginsenosides after single oral administrations of RGE (2 g/kg) in mice. The plasma concentrations of CK, PPD, and PPT were not detectable without change in GRb1, GRb2, and GRc in this group. LAB supplementation (1 billion CFU/2 g/kg/day for 1 week) after the amoxicillin treatment in mice restored the ginsenoside metabolism and the plasma concentrations of ginsenosides to the control level. In conclusion, the alterations in the gut microbiota environment could change the ginsenoside metabolism and plasma concentrations of ginsenosides. Therefore, the supplementation of LAB with oral administrations of RGE would help increase plasma concentrations of deglycosylated ginsenosides such as CK, PPD, and PPT. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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15 pages, 2229 KiB

Open AccessArticle

Comprehensive Investigation of Stereoselective Food Drug Interaction Potential of Resveratrol on Nine P450 and Six UGT Isoforms in Human Liver Microsomes

by Seung-Bae Ji, So-Young Park, Subin Bae, Hyung-Ju Seo, Sin-Eun Kim, Gyung-Min Lee, Zhexue Wu and Kwang-Hyeon Liu

Pharmaceutics 2021, 13(9), 1419; https://doi.org/10.3390/pharmaceutics13091419 - 7 Sep 2021

Cited by 6 | Viewed by 3068

Abstract

The stereoselectivity of the food drug inhibition potential of resveratrol on cytochrome P450s and uridine 5′-diphosphoglucuronosyl transferases was investigated in human liver microsomes. Resveratrol enantiomers showed stereoselective inhibition of CYP2C9, CYP3A, and UGT1A1. The inhibitions of CYP1A2, CYP2B6, and CYP2C19 by resveratrol were [...] Read more.

The stereoselectivity of the food drug inhibition potential of resveratrol on cytochrome P450s and uridine 5′-diphosphoglucuronosyl transferases was investigated in human liver microsomes. Resveratrol enantiomers showed stereoselective inhibition of CYP2C9, CYP3A, and UGT1A1. The inhibitions of CYP1A2, CYP2B6, and CYP2C19 by resveratrol were stereo-nonselective. The estimated K_i values determined for CYP1A2 were 13.8 and 9.2 μM for trans- and cis-resveratrol, respectively. Trans-resveratrol noncompetitively inhibited CYP3A and UGT1A1 activities with K_i values of 23.8 and 27.4 μM, respectively. Trans-resveratrol inhibited CYP1A2, CYP2C19, CYP2E1, and CYP3A in a time-dependent manner with K_i shift values >2.0, while cis-resveratrol time-dependently inhibited CYP2C19 and CYP2E1. The time-dependent inhibition of trans-resveratrol against CYP3A4, CYP2E1, CYP2C19, and CYP1A2 was elucidated using glutathione as a trapping reagent. This information helped the prediction of food drug interaction potentials between resveratrol and co-administered drugs which are mainly metabolized by UGT1A1, CYP1A2, CYP2C19, CYP2E1, and CYP3A. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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13 pages, 1930 KiB

Open AccessArticle

Evaluation of Pharmacokinetics and Pharmacodynamics of Deferasirox in Pediatric Patients

by Laura Galeotti, Francesco Ceccherini, Carmen Fucile, Valeria Marini, Antonello Di Paolo, Natalia Maximova and Francesca Mattioli

Pharmaceutics 2021, 13(8), 1238; https://doi.org/10.3390/pharmaceutics13081238 - 11 Aug 2021

Cited by 7 | Viewed by 3060

Abstract

Background: Deferasirox (DFX) is commonly used to reduce the chronic iron overload (IO) in pediatric patients. However, the drug is characterized by a large pharmacokinetic variability and approximately 10% of patients may discontinue the treatment due to toxicities. Therefore, the present retrospective study [...] Read more.

Background: Deferasirox (DFX) is commonly used to reduce the chronic iron overload (IO) in pediatric patients. However, the drug is characterized by a large pharmacokinetic variability and approximately 10% of patients may discontinue the treatment due to toxicities. Therefore, the present retrospective study investigated possible correlations between DFX pharmacokinetics and drug-associated toxicities in 39 children (26 males), aged 2–17 years, who underwent an allogeneic hematopoietic stem cell transplantation. Methods: IO was diagnosed by an abdominal magnetic resonance imaging and DFX was started at a median dose of 500 mg/day. DFX plasma concentrations were measured by a high performance liquid chromatographic method with UV detection and they were analysed by nonlinear mixed-effects modeling. Results: The pharmacometric analysis demonstrated that DFX pharmacokinetics were significantly influenced by lean body mass (bioavailability and absorption constant), body weight (volume of distribution), alanine and aspartate transaminases, direct bilirubin, and serum creatinine (clearance). Predicted DFX minimum plasma concentrations (C_trough) accounted for 32.4 ± 23.2 mg/L (mean ± SD), and they were significantly correlated with hepatic/renal and hematological toxicities (p-value < 0.0001, T-test and Fisher’s exact tests) when C_trough threshold values of 7.0 and 11.5 mg/L were chosen, respectively. Conclusions: The population pharmacokinetic model described the interindividual variability and identified C_trough threshold values that were predictive of hepatic/renal and hematological toxicities associated with DFX. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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23 pages, 2270 KiB

Open AccessArticle

Effects of 1α,25-Dihydroxyvitamin D₃ on the Pharmacokinetics of Procainamide and Its Metabolite N-Acetylprocainamide, Organic Cation Transporter Substrates, in Rats with PBPK Modeling Approach

by Anusha Balla, Yoo-Seong Jeong, Hyo-Jung Kim, Yun-Jong Lee, Suk-Jae Chung, Yoon-Jee Chae and Han-Joo Maeng

Pharmaceutics 2021, 13(8), 1133; https://doi.org/10.3390/pharmaceutics13081133 - 25 Jul 2021

Cited by 8 | Viewed by 2660

Abstract

In this study, possible changes in the expression of rat organic cationic transporters (rOCTs) and rat multidrug and toxin extrusion proteins (rMATEs) following treatment with 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) were investigated. Rats received intraperitoneal administrations of 1,25(OH)₂D [...] Read more.

In this study, possible changes in the expression of rat organic cationic transporters (rOCTs) and rat multidrug and toxin extrusion proteins (rMATEs) following treatment with 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) were investigated. Rats received intraperitoneal administrations of 1,25(OH)₂D₃ for four consecutive days, and the tissues of interest were collected. The mRNA expression of rOCT1 in the kidneys was significantly increased in 1,25(OH)₂D₃-treated rats compared with the control rats, while the mRNA expressions of rOCT2 and rMATE1 in the kidneys, rOCT1 and N-acetyltransferase-II (NAT-II) in the liver, and rOCT3 in the heart were significantly decreased. Changes in the protein expression of hepatic rOCT1 and renal rOCT2 and rMATE1 were confirmed by western blot analysis. We further evaluated the pharmacokinetics of procainamide (PA) hydrochloride and its major metabolite N-acetyl procainamide (NAPA) in the presence of 1,25(OH)₂D₃. When PA hydrochloride was administered intravenously at a dose 10 mg/kg to 1,25(OH)₂D₃-treated rats, a significant decrease in renal and/or non-renal clearance of PA and NAPA was observed. A physiological model for the pharmacokinetics of PA and NAPA in rats was useful for linking changes in the transcriptional and translational expressions of rOCTs and rMATE1 transporters to the altered pharmacokinetics of the drugs. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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15 pages, 1769 KiB

Open AccessArticle

Changes in the Pharmacokinetics and Pharmacodynamics of Sildenafil in Cigarette and Cannabis Smokers

by Mohammed Murtadha, Mohamed Ahmed Raslan, Sarah Farid Fahmy and Nagwa Ali Sabri

Pharmaceutics 2021, 13(6), 876; https://doi.org/10.3390/pharmaceutics13060876 - 13 Jun 2021

Cited by 8 | Viewed by 5272

Abstract

Sildenafil citrate, a widely-used oral therapy for erectile dysfunction, is a cytochrome P3A4 (CYP3A4) enzyme substrate. Studies have reported that this substrate has an inhibitory effect on CYP3A4 enzymes in long-term cigarette and cannabis smokers, which predominantly mediate the hepatic elimination of sildenafil. [...] Read more.

Sildenafil citrate, a widely-used oral therapy for erectile dysfunction, is a cytochrome P3A4 (CYP3A4) enzyme substrate. Studies have reported that this substrate has an inhibitory effect on CYP3A4 enzymes in long-term cigarette and cannabis smokers, which predominantly mediate the hepatic elimination of sildenafil. Cigarette and/or cannabis smoking could therefore alter the exposure of sildenafil. The aim of this study was to examine the effect of smoking cigarettes and/or cannabis on the pharmacokinetics, pharmacodynamics, safety and tolerability of sildenafil. Thirty-six healthy human subjects were equally divided into three groups: non-smokers, cigarette smokers and cannabis smokers. Each group was administered a single dose of sildenafil (50 mg tablets). The primary outcome measures included the maximum concentration of sildenafil in plasma (C_max), the elimination half-life (t1/2) and the area under the plasma concentration time curve from zero to time (AUC_0–t). The pharmacodynamics were assessed by the International Index of Erectile Function (IIEF-5). The exposure of sildenafil (AUC_0–t) showed a statistically significant increase in cigarette smokers (1156 ± 542 ng·h/mL) of 61% (p < 0.05) while in cannabis smokers (967 ± 262 ng·h/mL), a non-significant increase in AUC_0–t of 35% (p > 0.05) was observed relative to non-smokers (717 ± 311 ng·h/mL). Moreover, the C_max of sildenafil increased by 63% (p < 0.05) and 22% (p > 0.05) in cigarette smokers and cannabis smokers, respectively. Cigarette smoking increases the exposure of sildenafil to a statistically significant level with no effect on its pharmacodynamics, safety and tolerability. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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14 pages, 1528 KiB

Open AccessArticle

Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

by Yoo-Seong Jeong, Min-Soo Kim, Nora Lee, Areum Lee, Yoon-Jee Chae, Suk-Jae Chung and Kyeong-Ryoon Lee

Pharmaceutics 2021, 13(6), 813; https://doi.org/10.3390/pharmaceutics13060813 - 29 May 2021

Cited by 12 | Viewed by 5711

Abstract

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models [...] Read more.

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (V_SS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The C_max, AUC_last, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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19 pages, 3392 KiB

Open AccessArticle

Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

by Bettina Gerner and Oliver Scherf-Clavel

Pharmaceutics 2021, 13(6), 778; https://doi.org/10.3390/pharmaceutics13060778 - 22 May 2021

Cited by 18 | Viewed by 4759

Abstract

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions [...] Read more.

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim^® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (C_max) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for C_max). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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15 pages, 1279 KiB

Open AccessArticle

Pharmacokinetic Drug Interaction between Tofacitinib and Voriconazole in Rats

by Ji-Sang Lee, Hyo-Sung Kim, Yong-Seob Jung, Hyeon-Gyeom Choi and So-Hee Kim

Pharmaceutics 2021, 13(5), 740; https://doi.org/10.3390/pharmaceutics13050740 - 18 May 2021

Cited by 5 | Viewed by 3482

Abstract

Fungal infections are prevalent in patients with immune diseases. Voriconazole, a triazole antifungal drug, inhibits the cytochromes CYP3A4 and CYP2C, and tofacitinib, a Janus kinase inhibitor for the treatment of rheumatoid arthritis, is metabolized by CYP3A4 and CYP2C19 in humans. Here, we investigated [...] Read more.

Fungal infections are prevalent in patients with immune diseases. Voriconazole, a triazole antifungal drug, inhibits the cytochromes CYP3A4 and CYP2C, and tofacitinib, a Janus kinase inhibitor for the treatment of rheumatoid arthritis, is metabolized by CYP3A4 and CYP2C19 in humans. Here, we investigated their interaction during simultaneous administration of both drugs to rats, either intravenously or orally. The area under the plasma concentration–time curve from time zero to time infinity (AUC) of tofacitinib was significantly greater, by 166% and 171%, respectively, and the time-averaged non-renal clearance (CL_NR) of tofacitinib was significantly slower (59.5%) than that for tofacitinib alone. An in vitro metabolism study showed non-competitive inhibition of tofacitinib metabolism in the liver and intestine by voriconazole. The concentration/apparent inhibition constant (K_i) ratios of voriconazole were greater than two, indicating that the inhibition of tofacitinib metabolism could be due to the inhibition of the CYP3A1/2 and CYP2C11 enzymes by voriconazole. The pharmacokinetics of voriconazole were not affected by the co-administration of tofacitinib. In conclusion, the significantly greater AUC and slower CL_NR of tofacitinib after intravenous and oral administration of both drugs were attributable to the non-competitive inhibition of tofacitinib metabolism via CYP3A1/2 and CYP2C11 by voriconazole in rats. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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23 pages, 3312 KiB

Open AccessArticle

A Whole-Body Physiologically Based Pharmacokinetic Model Characterizing Interplay of OCTs and MATEs in Intestine, Liver and Kidney to Predict Drug-Drug Interactions of Metformin with Perpetrators

by Yiting Yang, Zexin Zhang, Ping Li, Weimin Kong, Xiaodong Liu and Li Liu

Pharmaceutics 2021, 13(5), 698; https://doi.org/10.3390/pharmaceutics13050698 - 11 May 2021

Cited by 9 | Viewed by 3876

Abstract

Transmembrane transport of metformin is highly controlled by transporters including organic cation transporters (OCTs), plasma membrane monoamine transporter (PMAT), and multidrug/toxin extrusions (MATEs). Hepatic OCT1, intestinal OCT3, renal OCT2 on tubule basolateral membrane, and MATE1/2-K on tubule apical membrane coordinately work to control [...] Read more.

Transmembrane transport of metformin is highly controlled by transporters including organic cation transporters (OCTs), plasma membrane monoamine transporter (PMAT), and multidrug/toxin extrusions (MATEs). Hepatic OCT1, intestinal OCT3, renal OCT2 on tubule basolateral membrane, and MATE1/2-K on tubule apical membrane coordinately work to control metformin disposition. Drug–drug interactions (DDIs) of metformin occur when co-administrated with perpetrators via inhibiting OCTs or MATEs. We aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model characterizing interplay of OCTs and MATEs in the intestine, liver, and kidney to predict metformin DDIs with cimetidine, pyrimethamine, trimethoprim, ondansetron, rabeprazole, and verapamil. Simulations showed that co-administration of perpetrators increased plasma exposures to metformin, which were consistent with clinic observations. Sensitivity analysis demonstrated that contributions of the tested factors to metformin DDI with cimetidine are gastrointestinal transit rate > inhibition of renal OCT2 ≈ inhibition of renal MATEs > inhibition of intestinal OCT3 > intestinal pH > inhibition of hepatic OCT1. Individual contributions of transporters to metformin disposition are renal OCT2 ≈ renal MATEs > intestinal OCT3 > hepatic OCT1 > intestinal PMAT. In conclusion, DDIs of metformin with perpetrators are attributed to integrated effects of inhibitions of these transporters. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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15 pages, 2337 KiB

Open AccessArticle

Ginsenoside Absorption Rate and Extent Enhancement of Black Ginseng (CJ EnerG) over Red Ginseng in Healthy Adults

by Saebyul Yoo, Bom-I Park, Do-hyun Kim, Sooyoung Lee, Seung-hoon Lee, Wang-Seob Shim, Yong Ki Seo, Kimoon Kang, Kyung-Tae Lee, Sung-Vin Yim, Do Yu Soung and Bo-Hyung Kim

Pharmaceutics 2021, 13(4), 487; https://doi.org/10.3390/pharmaceutics13040487 - 2 Apr 2021

Cited by 18 | Viewed by 5033

Abstract

Red ginseng (RG) and black ginseng (BG, CJ EnerG) were prepared from fresh ginseng using one and nine cycles of steaming and drying, respectively. This process reduces the molecular weight (MW) of ginsenoside-active compounds in ginseng by removing sugar moieties from their dammaranes. [...] Read more.

Red ginseng (RG) and black ginseng (BG, CJ EnerG) were prepared from fresh ginseng using one and nine cycles of steaming and drying, respectively. This process reduces the molecular weight (MW) of ginsenoside-active compounds in ginseng by removing sugar moieties from their dammaranes. We compared the pharmacokinetic characteristics of ginsenosides between BG comprising mainly low-MW ginsenosides (Rg3, Rg5, Rk1, and Rh1) and RG that predominantly contains high-MW ginsenosides (Rb1, Rb2, Rc, Rd, Re, and Rg1). The safety profiles and tolerability were also studied using a randomized, double-blind, single-dose, crossover clinical trial. A combination of Rb1, Rg1, and Rg3, well-known representative and functional RG components, exhibited a 1 h faster absorption rate (T_max) and 58% higher exposure (24 h area under the concentration–time curve, AUC₂₄) in BG than in RG. Furthermore, the combination of Rg3, Rg5, and Rk1, the major and most efficient components in BG, displayed 824% higher absorption (AUC₂₄) in BG than in RG. The total ginsenoside showed a 5 h rapid intestinal absorption (T_max) and 79% greater systemic exposure (AUC₂₄) in BG than in RG. No clinically significant findings were observed in terms of safety or tolerability. Thus, BG extract was more effective than RG extract. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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19 pages, 2456 KiB

Open AccessArticle

Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

by Tung-Hu Tsai, Yu-Jen Chen, Li-Ying Wang and Chen-Hsi Hsieh

Pharmaceutics 2021, 13(3), 386; https://doi.org/10.3390/pharmaceutics13030386 - 13 Mar 2021

Cited by 7 | Viewed by 2407

Abstract

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and [...] Read more.

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)_regorafenib by 74% (p = 0.001) in the RT_{2 Gy × 3 fraction (f’x)} group and by 69% (p = 0.001) in the RT_{9 Gy × 3 f’x} group. The AUC_regorafenib was increased by 182.8% (p = 0.011) in the sequential RT_{2Gy × 1 f’x} group and by 213.2% (p = 0.016) in the sequential RT_{9Gy × 1 f’x} group. Both concurrent regimens, RT_{2Gy × 3 f’x} and RT_{9Gy × 3 f’x}, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib _{× 3 d}) group. The concurrent regimens, both RT_{2Gy × 3 f’x} and RT_{9Gy × 3 f’x}, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT). Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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14 pages, 1103 KiB

Open AccessArticle

Inhibitory Effects of Schisandra Lignans on Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyl Transferases in Human Liver Microsomes

by Hyung-Ju Seo, Seung-Bae Ji, Sin-Eun Kim, Gyung-Min Lee, So-Young Park, Zhexue Wu, Dae Sik Jang and Kwang-Hyeon Liu

Pharmaceutics 2021, 13(3), 371; https://doi.org/10.3390/pharmaceutics13030371 - 10 Mar 2021

Cited by 15 | Viewed by 2993

Abstract

Schisandra chinensis has been widely used as a traditional herbal medicine to treat chronic coughs, fatigue, night sweats, and insomnia. Numerous bioactive components including lignans have been identified in this plant. Lignans with a dibenzocyclooctadiene moiety have been known to possess anti-cancer, anti-inflammatory, [...] Read more.

Schisandra chinensis has been widely used as a traditional herbal medicine to treat chronic coughs, fatigue, night sweats, and insomnia. Numerous bioactive components including lignans have been identified in this plant. Lignans with a dibenzocyclooctadiene moiety have been known to possess anti-cancer, anti-inflammatory, and hepatoprotective activity. Fragmentary studies have reported the ability of some lignans to modulate some cytochrome P450 (P450) enzymes. Herein, we investigated the drug interaction potential of six dibenzocyclooctadiene lignans (schisandrin, gomisin A, B, C, and N, and wuweizisu C) on nine P450 enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) and six uridine 5′-diphosphoglucuronosyl transferase (UGT) enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) using human liver microsomes. We found that lignans with one or two methylenedioxyphenyl groups inhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 activities in a time- and concentration-dependent like their CYP3A inhibition. In comparison, these lignans do not induce time-dependent inhibition of CYP1A2, CYP2A6, and CYP2D6. The time-dependent inhibition of gomisin A against CYP2C8, CYP2C19, and CYP3A4 was also elucidated using glutathione as a trapping reagent of reactive carbene metabolites given that gomisin A strongly inhibits these P450 enzymes in a time-dependent manner. A glutathione conjugate of gomisin A was generated in reactions with human recombinant CYP2C8, CYP2C19, and CYP3A4. This suggests that the time-dependent inhibition of gomisin A against CYP2C8, CYP2C9, and CYP3A4 is due to the production of carbene reactive metabolite. Six of the lignans we tested inhibited the activities of six UGT to a limited extent (IC₅₀ > 15 μM). This information may aid the prediction of possible drug interactions between Schisandra lignans and any co-administered drugs which are mainly metabolized by P450s. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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17 pages, 1752 KiB

Open AccessArticle

Involvement of Organic Anion Transporters in the Pharmacokinetics and Drug Interaction of Rosmarinic Acid

by Yun Ju Kang, Chul Haeng Lee, Soo-Jin Park, Hye Suk Lee, Min-Koo Choi and Im-Sook Song

Pharmaceutics 2021, 13(1), 83; https://doi.org/10.3390/pharmaceutics13010083 - 9 Jan 2021

Cited by 13 | Viewed by 3200

Abstract

We investigated the involvement of drug transporters in the pharmacokinetics of rosmarinic acid in rats as well as the transporter-mediated drug interaction potential of rosmarinic acid in HEK293 cells overexpressing clinically important solute carrier transporters and also in rats. Intravenously injected rosmarinic acid [...] Read more.

We investigated the involvement of drug transporters in the pharmacokinetics of rosmarinic acid in rats as well as the transporter-mediated drug interaction potential of rosmarinic acid in HEK293 cells overexpressing clinically important solute carrier transporters and also in rats. Intravenously injected rosmarinic acid showed bi-exponential decay and unchanged rosmarinic acid was mainly eliminated by urinary excretion, suggesting the involvement of transporters in its renal excretion. Rosmarinic acid showed organic anion transporter (OAT)1-mediated active transport with a K_m of 26.5 μM and a V_max of 69.0 pmol/min in HEK293 cells overexpressing OAT1, and the plasma concentrations of rosmarinic acid were increased by the co-injection of probenecid because of decreased renal excretion due to OAT1 inhibition. Rosmarinic acid inhibited the transport activities of OAT1, OAT3, organic anion transporting polypeptide (OATP)1B1, and OATP1B3 with IC₅₀ values of 60.6 μM, 1.52 μM, 74.8 μM, and 91.3 μM, respectively, and the inhibitory effect of rosmarinic acid on OAT3 transport activity caused an in vivo pharmacokinetic interaction with furosemide by inhibiting its renal excretion and by increasing its plasma concentration. In conclusion, OAT1 and OAT3 are the major transporters that may regulate the pharmacokinetic properties of rosmarinic acid and may cause herb-drug interactions with rosmarinic acid, although their clinical relevance awaits further evaluation. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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Review

Jump to: Research

9 pages, 662 KiB

Open AccessReview

The Effect of CYP2D6 Phenotypes on the Pharmacokinetics of Propafenone: A Systematic Review and Meta-Analysis

by Quyen Thi Tran, In-hwan Baek, Na-young Han, Hwi-yeol Yun and Jung-woo Chae

Pharmaceutics 2022, 14(7), 1446; https://doi.org/10.3390/pharmaceutics14071446 - 11 Jul 2022

Cited by 4 | Viewed by 2013

Abstract

Propafenone (PPF) is a class 1C antiarrhythmic agent mainly metabolized by cytochrome (CYP) 2D6, CYP1A2, and CYP3A4. Previous studies have shown that CYP2D6 polymorphism influences the pharmacokinetics (PK) of PPF. However, the small sample sizes of PK studies can lead to less precise [...] Read more.

Propafenone (PPF) is a class 1C antiarrhythmic agent mainly metabolized by cytochrome (CYP) 2D6, CYP1A2, and CYP3A4. Previous studies have shown that CYP2D6 polymorphism influences the pharmacokinetics (PK) of PPF. However, the small sample sizes of PK studies can lead to less precise estimates of the PK parameters. Thus, this meta-analysis was performed to merge all current PK studies of PPF to determine the effects of the CYP2D6 phenotype more accurately on the PPF PK profile. We searched electronic databases for published studies to investigate the association between the PPF PK and CYP2D6 phenotype. Four PK-related outcomes were included: area under the time–concentration curve (AUC), maximum concentration (C_max), apparent clearance (CL/F), and half-life (t_1/2). A total of five studies were included in this meta-analysis (n = 56). Analyses were performed to compare PK parameters between poor metabolizers (PMs) versus extensive metabolizers (EMs). PPF has a non-linear pharmacokinetics; therefore, analyses were performed according to dose (300 mg and 400 mg). At 300 mg, the AUC mean (95% CI), C_max, and t_1/2 of PPF in PMs were 15.9 (12.5–19.2) µg·h/mL, 1.10 (0.796–1.40) µg/mL, and 12.8 (11.3–14.3) h, respectively; these values were 2.4-, 11.2-, and 4.7-fold higher than those in the EM group, respectively. At 400 mg, a comparison was performed between S- and R-enantiomers. The CL/F was approximately 1.4-fold higher for the R-form compared with the S-form, which was a significant difference. This study demonstrated that CYP2D6 metabolizer status could significantly affect the PPF PK profile. Adjusting the dose of PPF according to CYP2D6 phenotype would help to avoid adverse effects and ensure treatment efficacy. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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16 pages, 360 KiB

Open AccessReview

Interaction of Energy Drinks with Prescription Medication and Drugs of Abuse

by Olga Hladun, Esther Papaseit, Soraya Martín, Ana Maria Barriocanal, Lourdes Poyatos, Magí Farré and Clara Pérez-Mañá

Pharmaceutics 2021, 13(10), 1532; https://doi.org/10.3390/pharmaceutics13101532 - 22 Sep 2021

Cited by 10 | Viewed by 5366

Abstract

In recent years, the consumption of energy drinks (EDs) has become increasingly popular, especially among adolescents. Caffeine, a psychostimulant, is the main compound of EDs which also contain other substances with pharmacological effects. This review aims to compile current evidence concerning the potential [...] Read more.

In recent years, the consumption of energy drinks (EDs) has become increasingly popular, especially among adolescents. Caffeine, a psychostimulant, is the main compound of EDs which also contain other substances with pharmacological effects. This review aims to compile current evidence concerning the potential interactions between EDs, medicines, and drugs of abuse as they are frequently consumed in combination. The substances involved are mainly substrates, inductors or inhibitors of CYP1A2, psychostimulants, alcohol and other depressant drugs. Furthermore, intoxications reported with EDs and other substances have also been screened to describe acute toxicity. The results of our review show that the consumption of both EDs alone and in combination is not as safe as previously thought. Health professionals and consumers need to be aware of the potential interactions of these drinks as well as the absence of long-term safety data. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

23 pages, 1400 KiB

Open AccessReview

Contribution of CYP2D6 Functional Activity to Oxycodone Efficacy in Pain Management: Genetic Polymorphisms, Phenoconversion, and Tissue-Selective Metabolism

by Malavika Deodhar, Jacques Turgeon and Veronique Michaud

Pharmaceutics 2021, 13(9), 1466; https://doi.org/10.3390/pharmaceutics13091466 - 14 Sep 2021

Cited by 14 | Viewed by 7377

Abstract

Oxycodone is a widely used opioid for the management of chronic pain. Analgesic effects observed following the administration of oxycodone are mediated mostly by agonistic effects on the μ-opioid receptor. Wide inter-subject variability observed in oxycodone efficacy could be explained by polymorphisms in [...] Read more.

Oxycodone is a widely used opioid for the management of chronic pain. Analgesic effects observed following the administration of oxycodone are mediated mostly by agonistic effects on the μ-opioid receptor. Wide inter-subject variability observed in oxycodone efficacy could be explained by polymorphisms in the gene coding for the μ-opioid receptor (OPRM1). In humans, oxycodone is converted into several metabolites, particularly into oxymorphone, an active metabolite with potent μ-opioid receptor agonist activity. The CYP2D6 enzyme is principally responsible for the conversion of oxycodone to oxymorphone. The CYP2D6 gene is highly polymorphic with encoded protein activities, ranging from non-functioning to high-functioning enzymes. Several pharmacogenetic studies have shown the importance of CYP2D6-mediated conversion of oxycodone to oxymorphone for analgesic efficacy. Pharmacogenetic testing could optimize oxycodone therapy and help achieve adequate pain control, avoiding harmful side effects. However, the most recent Clinical Pharmacogenetics Implementation Consortium guidelines fell short of recommending pharmacogenomic testing for oxycodone treatment. In this review, we (1) analyze pharmacogenomic and drug-interaction studies to delineate the association between CYP2D6 activity and oxycodone efficacy, (2) review evidence from CYP3A4 drug-interaction studies to untangle the nature of oxycodone metabolism and its efficacy, (3) report on the current knowledge linking the efficacy of oxycodone to OPRM1 variants, and (4) discuss the potential role of CYP2D6 brain expression on the local formation of oxymorphone. In conclusion, we opine that pharmacogenetic testing, especially for CYP2D6 with considerations of phenoconversion due to concomitant drug administration, should be appraised to improve oxycodone efficacy. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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43 pages, 1489 KiB

Open AccessReview

Herbal Medicine for Pain Management: Efficacy and Drug Interactions

by Behdad Jahromi, Iulia Pirvulescu, Kenneth D. Candido and Nebojsa Nick Knezevic

Pharmaceutics 2021, 13(2), 251; https://doi.org/10.3390/pharmaceutics13020251 - 11 Feb 2021

Cited by 38 | Viewed by 10408

Abstract

Complementary and alternative medicines such as herbal medicines are not currently part of the conventional medical system. As the popularity of and global market for herbal medicine grows among all age groups, with supporting scientific data and clinical trials, specific alternative treatments such [...] Read more.

Complementary and alternative medicines such as herbal medicines are not currently part of the conventional medical system. As the popularity of and global market for herbal medicine grows among all age groups, with supporting scientific data and clinical trials, specific alternative treatments such as herbal medicine can be reclassified as a practice of conventional medicine. One of the most common conditions for which adults use herbal medicine is pain. However, herbal medicines carry safety concerns and may impact the efficacy of conventional therapies. Unfortunately, mechanisms of action are poorly understood, and their use is unregulated and often underreported to medical professionals. This review aims to compile common and available herbal medicines which can be used as an alternative to or in combination with conventional pain management approaches. Efficacy and safety are assessed through clinical studies on pain relief. Ensuing herb–drug interactions such as cytochrome modulation, additive and synergistic effects, and contraindications are discussed. While self-management has been recognized as part of the overall treatment strategy for patients suffering from chronic pain, it is important for practitioners to be able to also optimize and integrate herbal medicine and, if warranted, other complementary and alternative medicines into their care. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Interactions)

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