Research

21 pages, 5479 KiB

Open AccessEditor’s ChoiceArticle

Effect of Gut Microbiota on the Pharmacokinetics of Nifedipine in Spontaneously Hypertensive Rats

by Rong Zhou, Haijun Yang, Peng Zhu, Yujie Liu, Yanjuan Zhang, Wei Zhang, Honghao Zhou, Xiong Li and Qing Li

Pharmaceutics 2023, 15(8), 2085; https://doi.org/10.3390/pharmaceutics15082085 - 03 Aug 2023

Viewed by 1244

Abstract

The pharmacokinetic variability of nifedipine widely observed in the clinic cannot be fully explained by pharmacogenomics. As a new factor affecting drug metabolism, how the gut microbiota affects the pharmacokinetics of nifedipine needs to be explored. Spontaneously hypertensive rats (SHRs) have been commonly [...] Read more.

The pharmacokinetic variability of nifedipine widely observed in the clinic cannot be fully explained by pharmacogenomics. As a new factor affecting drug metabolism, how the gut microbiota affects the pharmacokinetics of nifedipine needs to be explored. Spontaneously hypertensive rats (SHRs) have been commonly used in hypertension-related research and served as the experimental groups; Wistar rats were used as control groups. In this study, the bioavailability of nifedipine decreased by 18.62% (p < 0.05) in the SHRs compared with the Wistar rats. Changes in microbiota were associated with the difference in pharmacokinetics. The relative abundance of Bacteroides dorei was negatively correlated with AUC_0–t (r = −0.881, p = 0.004) and C_max (r = −0.714, p = 0.047). Analysis of serum bile acid (BA) profiles indicated that glycoursodeoxycholic acid (GUDCA) and glycochenodeoxycholic acid (GCDCA) were significantly increased in the SHRs. Compared with the Wistar rats, the expressions of CYP3A1 and PXR were upregulated and the enzyme activity of CYP3A1 increased in the SHRs. Spearman’s rank correlation revealed that Bacteroides stercoris was negatively correlated with GUDCA (r = −0.7126, p = 0.0264) and GCDCA (r = −0.6878, p = 0.0339). Moreover, GUDCA was negatively correlated with C_max (r = −0.556, p = 0.025). In primary rat hepatocytes, GUDCA could induce the expressions of PXR target genes CYP3A1 and Mdr1a. Furthermore, antibiotic treatments in SHRs verified the impact of microbiota on the pharmacokinetics of nifedipine. Generally, gut microbiota affects the pharmacokinetics of nifedipine through microbial biotransformation or by regulating the enzyme activity of CYP3A1. Full article

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

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12 pages, 1548 KiB

Open AccessArticle

Physiologically Based Pharmacokinetic Modelling to Predict Imatinib Exposures in Cancer Patients with Renal Dysfunction: A Case Study

by Karen Rowland Yeo, Oliver Hatley, Ben G. Small and Trevor N. Johnson

Pharmaceutics 2023, 15(7), 1922; https://doi.org/10.3390/pharmaceutics15071922 - 11 Jul 2023

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Abstract

Imatinib is mainly metabolised by CYP3A4 and CYP2C8 and is extensively bound to α-acid glycoprotein (AAG). A physiologically based pharmacokinetic (PBPK) model for imatinib describing the CYP3A4-mediated autoinhibition during multiple dosing in gastrointestinal stromal tumor patients with normal renal function was previously reported. [...] Read more.

Imatinib is mainly metabolised by CYP3A4 and CYP2C8 and is extensively bound to α-acid glycoprotein (AAG). A physiologically based pharmacokinetic (PBPK) model for imatinib describing the CYP3A4-mediated autoinhibition during multiple dosing in gastrointestinal stromal tumor patients with normal renal function was previously reported. After performing additional verification, the PBPK model was applied to predict the exposure of imatinib after multiple dosing in cancer patients with varying degrees of renal impairment. In agreement with the clinical data, there was a positive correlation between AAG levels and imatinib exposure. A notable finding was that for recovery of the observed data in cancer patients with moderate RI (CrCL 20 to 39 mL/min), reductions of hepatic CYP3A4 and CYP2C8 abundances, which reflect the effects of RI, had to be included in the simulations. This was not the case for mild RI (CrCL 40 to 50 mL/min). The results support the finding of the clinical study, which demonstrated that both AAG levels and the degree of renal impairment are key components that contribute to the interpatient variability associated with imatinib exposure. As indicated in the 2020 FDA draft RI guidance, PBPK modelling could be used to support an expanded inclusion of patients with RI in clinical studies. Full article

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

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14 pages, 11124 KiB

Open AccessArticle

Roles of Human Liver Cytochrome P450 Enzymes in Tenatoprazole Metabolism

by 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

Cited by 3 | Viewed by 1607

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 [...] Read more.

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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15 pages, 7094 KiB

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

by 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 3 | Viewed by 1233

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 [...] Read more.

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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12 pages, 1137 KiB

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

by Louise Breuil, Nora Ziani, Sarah Leterrier, Gaëlle Hugon, Fabien Caillé, Viviane Bouilleret, Charles Truillet, Maud Goislard, Myriam El Biali, Martin Bauer, Oliver Langer, Sébastien Goutal and Nicolas Tournier

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

Cited by 2 | Viewed by 1457

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 [¹¹ [...] Read more.

[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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32 pages, 4982 KiB

Open AccessArticle

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

by David Malnoë, Olivier Fardel and Pascal Le Corre

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

Cited by 4 | Viewed by 1527

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 [...] Read more.

(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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15 pages, 2077 KiB

Open AccessArticle

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

by Yang Li, Yan Jin, Hanieh Taheri, Keith T. Schmidt, Alice A. Gibson, Stefan A. J. Buck, Eric D. Eisenmann, Ron H. J. Mathijssen, William D. Figg, Sharyn D. Baker, Alex Sparreboom and Shuiying Hu

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

Cited by 1 | Viewed by 1804

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 [...] Read more.

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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11 pages, 1499 KiB

Open AccessArticle

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

by Jin-Woo Park, Jong-Min Kim, Hwa-Young Lee, Jihyeon Noh, Kyoung-Ah Kim and Ji-Young Park

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

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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 [...] Read more.

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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