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Special Issue "Drug Metabolism/Transport and Pharmacokinetics, Volume II"

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 5475

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Prof. Dr. Im-Sook Song

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Guest Editor

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea
Interests: pharmacokinetic drug–drug interaction; pharmacokinetic herb–drug interaction; drug-metabolizing enzymes and transporters; pharmacokinetic/pharmacodynamics in drug development; oral bioavailability
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Dear Colleagues,

Clinically important phase I and II metabolizing enzymes and transporters from two major superfamilies, ABC (ATP binding cassette) and SLC (Solute carrier) transporters, are designated and the pivotal roles of drug metabolizing enzymes and drug transporters in the pharmacokinetics, pharmacogenomics, and drug-drug interactions have been recognized. Therefore, researchers and regulatory agencies have made an effort to understand the pharmacokinetics, pharmacogenomics, and drug–drug interactions with respect to mechanistic changes in these drug metabolizing enzymes and transporters. With a trend of polypills and increased use of medicinal food, concurrent administration of herbal drugs can cause serious adverse reactions with substrate drugs of metabolizing enzymes and transporters by the potential for the inhibition or induction of their activities. For this, the prediction and evaluation of the contribution of drug metabolizing enzymes and transporters to the pharmacokinetics and drug–drug interaction potential of drugs or drug candidates are important in clinics and in the drug development process.

It is the second volume of the Special Issue "Drug Metabolism/Transport and Pharmacokinetics", which has published with 15 excellent papers in 2019. This volume will highlight pharmacokinetics/drug–drug interactions and mechanistic understanding in relation to the drug metabolizing enzymes and drug transporters.

Prof. Dr. Im-Sook Song
Guest Editor

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Keywords

pharmacokinetics
phase I and II metabolizing enzymes
drug transporters
drug–drug interaction
herb–drug interaction
enzyme inhibition and induction

Published Papers (6 papers)

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Research

Open AccessArticle

Roles of Human Liver Cytochrome P450 Enzymes in Tenatoprazole Metabolism

Thien-Kim Le

Young Jin Park

Gun Su Cha

Fikri A. R. Hardiyanti Oktavia

Dong Hyun Kim

and

Chul-Ho Yun

Pharmaceutics 2023, 15(1), 23; https://doi.org/10.3390/pharmaceutics15010023 - 21 Dec 2022

Viewed by 796

Abstract

Tenatoprazole, a newly developed proton pump inhibitor candidate, was developed as an acid inhibitor for gastric acid hypersecretion disorders such as gastric ulcer and reflux esophagitis. It is known that tenatoprazole is metabolized to three major metabolites of 5′-hydroxy tenatoprazole, tenatoprazole sulfide, and tenatoprazole sulfone in human liver, primarily catalyzed by CYPs 2C19 and 3A4. While CYP2C19 prefers the hydroxylation of tenatoprazole at C-5′ position, CYP3A4 is mainly involved in sulfoxidation reaction to make tenatoprazole sulfone. Tenatoprazole sulfide is a major human metabolite of tenatoprazole and is formed spontaneously and non-enzymatically from tenatoprazole. However, its metabolic fate in the human liver is not fully known. Furthermore, no systematic metabolic study has been performed to study tenatoprazole or tenatoprazole sulfide. Here, we studied the functions of human cytochromes P450 in the metabolic pathway of tenatoprazole and tenatoprazole sulfide by using recombinant human P450s and human liver microsomes. Both CYP 2C19 and CYP3A4 showed distinct regioselective and stereospecific monooxygenation activities toward tenatoprazole and tenatoprazole sulfide. Furthermore, a new major metabolite of tenatoprazole sulfide was found, 1′-N-oxy-5′-hydroxytenatoprzole sulfide, which has never been reported. In conclusion, the metabolic fates of tenatoprazole and tenatoprazole sulfide should be considered in the clinical use of tenatoprazole. Full article

(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics, Volume II)

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Open AccessArticle

A Transversal Approach Combining In Silico, In Vitro and In Vivo Models to Describe the Metabolism of the Receptor Interacting Protein 1 Kinase Inhibitor Sibiriline

Romain Pelletier

Thomas Gicquel

Mélanie Simoes Eugenio

Pierre-Jean Ferron

Isabelle Morel

Claire Delehouzé

Marie-Thérèse Dimanche-Boitrel

Morgane Rousselot

and

Brendan Le Daré

Pharmaceutics 2022, 14(12), 2665; https://doi.org/10.3390/pharmaceutics14122665 - 30 Nov 2022

Cited by 1 | Viewed by 673

Abstract

Sibiriline is a novel drug inhibiting receptor-interacting protein 1 kinase (RIPK1) and necroptosis, a regulated form of cell death involved in several disease models. In this study, we aimed to investigate the metabolic fate of sibiriline in a cross-sectional manner using an in silico prediction, coupled with in vitro and in vivo experiments. In silico predictions were performed using GLORYx and Biotransformer 3.0 freeware; in vitro incubation was performed on differentiated human HepaRG cells, and in vivo experiments including a pharmacokinetic study were performed on mice treated with sibiriline. HepaRG culture supernatants and mice plasma samples were analyzed with ultra-high-performance liquid chromatography, coupled with tandem mass spectrometry (LC-HRMS/MS). The molecular networking bioinformatics tool applied to LC-HRMS/MS data allowed us to visualize the sibiriline metabolism kinetics. Overall, 14 metabolites, mostly produced by Phase II transformations (glucuronidation and sulfation) were identified. These data provide initial reassurance regarding the toxicology of this new RIPK1 inhibitor, although further studies are required. Full article

(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics, Volume II)

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Open AccessArticle

Impact of Cytochrome Induction or Inhibition on the Plasma and Brain Kinetics of [¹¹C]metoclopramide, a PET Probe for P-Glycoprotein Function at the Blood-Brain Barrier

and

Pharmaceutics 2022, 14(12), 2650; https://doi.org/10.3390/pharmaceutics14122650 - 30 Nov 2022

Viewed by 784

Abstract

[¹¹C]metoclopramide PET imaging provides a sensitive and translational tool to explore P-glycoprotein (P-gp) function at the blood-brain barrier (BBB). Patients with neurological diseases are often treated with cytochrome (CYP) modulators which may impact the plasma and brain kinetics of [¹¹C]metoclopramide. The impact of the CYP inducer carbamazepine or the CYP inhibitor ritonavir on the brain and plasma kinetics of [¹¹C]metoclopramide was investigated in rats. Data obtained in a control group were compared with groups that were either orally pretreated with carbamazepine (45 mg/kg twice a day for 7 days before PET) or ritonavir (20 mg/kg, 3 h before PET) (n = 4 per condition). Kinetic modelling was performed to estimate the brain penetration (V_T) of [¹¹C]metoclopramide. CYP induction or inhibition had negligible impact on the plasma kinetics and metabolism of [¹¹C]metoclopramide. Moreover, carbamazepine neither impacted the brain kinetics nor V_T of [¹¹C]metoclopramide (p > 0.05). However, ritonavir significantly increased V_T (p < 0.001), apparently behaving as an inhibitor of P-gp at the BBB. Our data suggest that treatment with potent CYP inducers such as carbamazepine does not bias the estimation of P-gp function at the BBB with [¹¹C]metoclopramide PET. This supports further use of [¹¹C]metoclopramide for studies in animals and patients treated with CYP inducers. Full article

(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics, Volume II)

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Open AccessArticle

Involvement of Transporters in Intestinal Drug–Drug Interactions of Oral Targeted Anticancer Drugs Assessed by Changes in Drug Absorption Time

David Malnoë

Olivier Fardel

and

Pascal Le Corre

Pharmaceutics 2022, 14(11), 2493; https://doi.org/10.3390/pharmaceutics14112493 - 17 Nov 2022

Cited by 3 | Viewed by 738

Abstract

(1) Background: Oral targeted anticancer drugs are victims of presystemic pharmacokinetic drug–drug interactions (DDI). Identification of the nature of these DDIs, i.e., enzyme-based or/and transporter-based, is challenging, since most of these drugs are substrates of intestinal and/or hepatic cytochrome P-450 enzymes and of intestinal membrane transporters. (2) Methods: Variations in mean absorption time (MAT) between DDIs and control period (MAT ratios < 0.77 or >1.30) have been proposed to implicate transporters in DDIs at the intestinal level. This methodology has been applied to a large set of oral targeted anticancer drugs (n = 54, involved in 77 DDI studies), from DDI studies available either in the international literature and/or in publicly accessible FDA files. (3) Results: Significant variations in MAT were evidenced in 33 DDI studies, 12 of which could be explained by modulation of an efflux transporter. In 21 DDI studies, modulation of efflux transporters could not explain the MAT variation, suggesting a possible relevant role of influx transporters in the intestinal absorption. (4) Conclusions: This methodology allows one to suggest the involvement of intestinal transporters in DDIs, and should be used in conjunction with in vitro methodologies to help understanding the origin of DDIs. Full article

(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics, Volume II)

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Open AccessArticle

A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug–Drug Interaction Liabilities

and

Pharmaceutics 2022, 14(9), 1933; https://doi.org/10.3390/pharmaceutics14091933 - 13 Sep 2022

Viewed by 1064

Abstract

In recent years, various endogenous compounds have been proposed as putative biomarkers for the hepatic uptake transporters OATP1B1 and OATP1B3 that have the potential to predict transporter-mediated drug–drug interactions (DDIs). However, these compounds have often been identified from top–down strategies and have not been fully utilized as a substitute for traditional DDI studies. In an attempt to eliminate observer bias in biomarker selection, we applied a bottom–up, untargeted metabolomics screening approach in mice and found that plasma levels of the conjugated bile acid chenodeoxycholate-24-glucuronide (CDCA-24G) are particularly sensitive to deletion of the orthologous murine transporter Oatp1b2 (31-fold increase vs. wild type) or the entire Oatp1a/1b(−/−)cluster (83-fold increased), whereas the humanized transgenic overexpression of hepatic OATP1B1 or OATP1B3 resulted in the partial restoration of transport function. Validation studies with the OATP1B1/OATP1B3 inhibitors rifampin and paclitaxel in vitro as well as in mice and human subjects confirmed that CDCA-24G is a sensitive and rapid response biomarker to dose-dependent transporter inhibition. Collectively, our study confirmed the ability of CDCA-24G to serve as a sensitive and selective endogenous biomarker of OATP1B-type transport function and suggests a template for the future development of biomarkers for other clinically important xenobiotic transporters. Full article

(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics, Volume II)

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Open AccessArticle

CYP3A5*3 and SLCO1B1 c.521T>C Polymorphisms Influence the Pharmacokinetics of Atorvastatin and 2-Hydroxy Atorvastatin

and

Pharmaceutics 2022, 14(7), 1491; https://doi.org/10.3390/pharmaceutics14071491 - 18 Jul 2022

Viewed by 815

Abstract

There is a large variability in individual responses to atorvastatin administration. This study assessed the pharmacogenetic effects of solute carrier organic anion transporter family member 1B1 (SLCO1B1, c.388A>G and c.521T>C) and cytochrome P450 3A5 (CYP3A5, CYP3A5*3) genetic polymorphisms on the pharmacokinetics of atorvastatin and its active metabolite, 2-hydroxy (2-OH) atorvastatin, in 46 individuals who were administered a clinically used single oral dosage of 80 mg. The C_max and AUC of atorvastatin in CYP3A5*3/*3 carriers were 2.6- and 2.8-fold higher, respectively, than those in CYP3A5*1/*1 carriers, and similar results were observed for 2-OH atorvastatin pharmacokinetics. SLCO1B1 c.521T>C also increased the AUC of atorvastatin and 2-OH atorvastatin. The AUC ratio of atorvastatin and 2-OH atorvastatin were not affected by SLCO1B1 c.388A>G or c.521T>C, whereas CYP3A5*3 reduced the AUC ratio. In an analysis evaluating the simultaneous effect of the SLCO1B1 c.521T>C and CYP3A5*3 polymorphisms, SLCO1B1 c.521TT/CYP3A5*1/*1 carriers showed lower C_max and AUC values for atorvastatin and 2-OH atorvastatin than in individuals with the SLCO1B1 c.521T>C and/or CYP3A5*3 genotypes. Among the participants with the SLCO1B1 c.521TT genotype, the CYP3A5*3 carriers had a higher systemic exposure to atorvastatin and 2-OH atorvastatin than the CYP3A5*1/*1 carriers. Thus, SLCO1B1 c.521T>C and CYP3A5*3 polymorphisms affect the pharmacokinetics of atorvastatin and 2-OH atorvastatin. Full article

(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics, Volume II)

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