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New Analytical Techniques and Methods in Drug Metabolism and Pharmacokinetics
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New Analytical Techniques and Methods in Drug Metabolism and Pharmacokinetics

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Analytical Chemistry".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 18266

Special Issue Editor

Prof. Dr. Young G. Shin

E-Mail Website
Guest Editor
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon, Republic of Korea
Interests: drug metabolism; metabolite identification; pharmacokinetics; antibody–drug conjugates; albumin–drug conjugates; small molecules; ASO; SiRNA; PROTAC; CAR-T
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug metabolism and pharmacokinetics play a critical role in drug discovery and development. Regardless of modalities, the most common challenge faced during their drug development process is how to evaluate their absorption, distribution, metabolism, and excretion (ADME) process in silico, in vitro, in vivo, and eventually to translate the outcome in humans. In addition, full characterization of metabolite identification for the drug candidate is another challenge when the structure of the drug candidate is quite complicated. Scientists also often struggle with a drug candidate’s unfavorable physicochemical properties that lead to poor pharmacokinetics (PK) and biopharmaceutical profiles, and in some cases, it is very challenging to even develop an assay to evaluate the bioequivalence (BE)/bioavailability (BA), etc.  

Therefore, this Special Issue is intended to highlight the recent advancements and trends of new analytical techniques and methods, particularly from the drug metabolism and pharmacokinetics perspectives. Research papers and reviews illustrating the interesting developments related to in silico/in vitro/in vivo ADME (and/or PK) sample preparation, separation science, spectroscopic techniques, as well as any novel techniques for small molecules, peptides, monoclonal antibodies, antibody–drug conjugates, RNAi, PNA, aptamers, CRISPR/Cas9, etc. are all welcome.

I would be delighted if you could respond to confirm your contribution and the proposed title in the next two weeks.

Prof. Young G. Shin
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug metabolism
  • pharmacokinetics
  • metabolite identification
  • ADME
  • method development for biological samples
  • bioequivalence and bioavailability
  • novel analytical method

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Published Papers (4 papers)

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Research

10 pages, 1982 KiB  
Article
Quantification of an Antibody-Conjugated Drug in Fat Plasma by an Affinity Capture LC-MS/MS Method for a Novel Prenyl Transferase-Mediated Site-Specific Antibody–Drug Conjugate
by Byeong ill Lee, Min-Ho Park, Jin-Ju Byeon, Seok-Ho Shin, Jangmi Choi, Yuri Park, Yun-Hee Park, Jeiwook Chae and Young G. Shin
Molecules 2020, 25(7), 1515; https://doi.org/10.3390/molecules25071515 - 26 Mar 2020
Cited by 22 | Viewed by 4853
Abstract
The novel prenyl transferase-mediated, site-specific, antibody–drug conjugate LCB14-0110 is comprised of a proprietary beta-glucuronide linker and a payload (Monomethyl auristatin F, MMAF, an inhibitor for tubulin polymerization) attached to human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab. A LC-MS/MS method was developed to [...] Read more.
The novel prenyl transferase-mediated, site-specific, antibody–drug conjugate LCB14-0110 is comprised of a proprietary beta-glucuronide linker and a payload (Monomethyl auristatin F, MMAF, an inhibitor for tubulin polymerization) attached to human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab. A LC-MS/MS method was developed to quantify the antibody-conjugated drug (acDrug) for in vitro linker stability and preclinical pharmacokinetic studies. The method consisted of affinity capture, enzymatic cleavage of acDrug, and LC-MS/MS analysis in the positive ion mode. A quadratic regression (weighted 1/concentration2), with the equation y = ax2 + bx + c, was used to fit calibration curves over the concentration range of 19.17~958.67 ng/mL for acDrug. The qualification run met the acceptance criteria of ±25% accuracy and precision values for quality control (QC) samples. The overall recovery was 42.61%. The dilution integrity was for a series of 5-fold dilutions with accuracy and precision values ranging within ±25%. The stability results indicated that acDrug was stable at all stability test conditions (short-term: 1 day, long-term: 10 months, Freeze/Thaw (F/T): 3 cycles). This qualified method was successfully applied to in vitro linker stability and pharmacokinetic case studies of acDrug in rats. Full article
(This article belongs to the Special Issue New Analytical Techniques and Methods in Drug Metabolism and Pharmacokinetics)
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12 pages, 1249 KiB  
Article
In Vitro, In Silico, and In Vivo Assessments of Pharmacokinetic Properties of ZM241385
by Jin-Ju Byeon, Min-Ho Park, Seok-Ho Shin, Yuri Park, Byeong ill Lee, Jang-mi Choi, Nahye Kim, Seo-jin Park, Min-jae Park, Jeong-hyeon Lim, Young-Guk Na and Young G. Shin
Molecules 2020, 25(5), 1106; https://doi.org/10.3390/molecules25051106 - 2 Mar 2020
Cited by 8 | Viewed by 4273
Abstract
Parkinson’s disease is one of the most common neurodegenerative diseases. Adenosine regulates the response to other neurotransmitters in the brain regions related to motor function. In the several subtypes of adenosine receptors, especially, adenosine 2A receptors (A2ARs) are involved in neurodegenerative [...] Read more.
Parkinson’s disease is one of the most common neurodegenerative diseases. Adenosine regulates the response to other neurotransmitters in the brain regions related to motor function. In the several subtypes of adenosine receptors, especially, adenosine 2A receptors (A2ARs) are involved in neurodegenerative conditions. ZM241385 is one of the selective non-xanthine A2AR antagonists with high affinity in the nanomolar range. This study describes the in vitro and in vivo pharmacokinetic properties of ZM241385 in rats. A liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qToF MS) method was developed for the determination of ZM241385 in rat plasma. In vivo IV administration studies showed that ZM241385 was rapidly eliminated in rats. However, the result of in vitro metabolic stability studies showed that ZM241385 had moderate clearance, suggesting that there is an extra clearance pathway in addition to hepatic clearance. In addition, in vivo PO administration studies demonstrated that ZM241385 had low exposure in rats. The results of semi-mass balance studies and the in silico PBPK modeling studies suggested that the low bioavailability of ZM241385 after oral administration in rats was due to the metabolism and by liver, kidney, and gut. Full article
(This article belongs to the Special Issue New Analytical Techniques and Methods in Drug Metabolism and Pharmacokinetics)
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18 pages, 3978 KiB  
Article
A Novel Eye Drop Candidate for Age-Related Macular Degeneration Treatment: Studies on its Pharmacokinetics and Distribution in Rats and Rabbits
by Eun-Jeong Choi, Go-Wun Choi, Ju Hee Kim, Hee-Woon Jang, Ju-Hee Lee, Hyun Ju Bae, Young Gwan Kim, Yong-Bok Lee and Hea-Young Cho
Molecules 2020, 25(3), 663; https://doi.org/10.3390/molecules25030663 - 4 Feb 2020
Cited by 4 | Viewed by 4083
Abstract
Age-related macular degeneration (AMD) is wearing down of macula of retina, causing a blur or loss of vision in the center of the visual field. It can be categorized into dry or wet AMD. Until now, medical treatments for dry AMD have not [...] Read more.
Age-related macular degeneration (AMD) is wearing down of macula of retina, causing a blur or loss of vision in the center of the visual field. It can be categorized into dry or wet AMD. Until now, medical treatments for dry AMD have not been developed yet. The aim of this study was to evaluate pharmacokinetics (PKs) and tissue distribution of CK41016, a novel candidate for dry AMD, after intravenous (IV) or eye drop administration in rats and rabbits. In addition, a simple and sensitive bioanalytical method for CK41016 using ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was developed. PK parameters were estimated by compartmental analysis using a WinNonlin® software version 8.1 (a Certara™ company). A PK model of CK41016 was well-described by the two-compartment model. The tissue-to-plasma partition coefficient (Kp) of CK41016 was the highest in the vitreous humor of rats and the cornea of rabbits after eye drop administration. In addition, the Caco-2 cell transporter assay confirmed that CK41016 was not an active substrate for the efflux transporter. In summary, the PKs and tissue distribution of CK41016 were successfully evaluated and investigated whether this drug was a substrate of efflux transporters. Full article
(This article belongs to the Special Issue New Analytical Techniques and Methods in Drug Metabolism and Pharmacokinetics)
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12 pages, 1287 KiB  
Article
Pharmacokinetic Characterization and Tissue Distribution of Fusion Protein Therapeutics by Orthogonal Bioanalytical Assays and Minimal PBPK Modeling
by Hiroshi Sugimoto, Susan Chen and Mark G. Qian
Molecules 2020, 25(3), 535; https://doi.org/10.3390/molecules25030535 - 26 Jan 2020
Cited by 9 | Viewed by 4109
Abstract
Characterization of pharmacokinetic (PK) properties and target tissue distribution of therapeutic fusion proteins (TFPs) are critical in supporting in vivo efficacy. We evaluated the pharmacokinetic profile of an investigational TFP consisting of human immunoglobulin G4 fused to the modified interferon alpha by orthogonal [...] Read more.
Characterization of pharmacokinetic (PK) properties and target tissue distribution of therapeutic fusion proteins (TFPs) are critical in supporting in vivo efficacy. We evaluated the pharmacokinetic profile of an investigational TFP consisting of human immunoglobulin G4 fused to the modified interferon alpha by orthogonal bioanalytical assays and applied minimal physiologically based pharmacokinetic (PBPK) modeling to characterize the TFP pharmacokinetics in mouse. The conventional ligand binding assay (LBA), immunocapture-liquid chromatography/tandem mass spectrometry (IC-LC/MS) detecting the human IgG4 peptide or the interferon alpha peptide were developed to measure the TFP concentrations in mouse plasma and tumor. The minimal PBPK model incorporated a tumor compartment model was used for data fitting. The plasma clearance measured by LBA and IC-LC/MS was comparable in the range of 0.5–0.6 mL/h/kg. However, the tumor exposure measured by the generic human IgG4 IC-LC/MS was significantly underestimated compared with the interferon alpha specific IC-LC/MS and LBA. Furthermore, the minimal PBPK model simultaneously captured the relationship between plasma and tissue exposure. We proposed the streamlined practical strategy to characterize the plasma exposure and tumor distribution of a TFP by both LBA and IC-LC/MS. The minimal PBPK modeling was established for better understanding of pharmacokinetic profile of investigational TFPs in the biotherapeutic discovery. Full article
(This article belongs to the Special Issue New Analytical Techniques and Methods in Drug Metabolism and Pharmacokinetics)
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