Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs

Abstract

Aim: To investigate the metabolism of GLS4, a heteroaryldihydropyrimidine compound with anti-hepatitis B virus activity, in dog and human liver microsomes in vitro and evaluate the effects of ketoconazole (a potent CYP3A inhibitor) or rifampicin (a potent CYP3A inducer) on GLS4 pharmacokinetics in dogs. Methods: Dog and human liver microsomes and CYP3A4 were incubated with [14 C]GLS4 for 15 min and then analyzed using a HPLCdynamic online radio flow detection method. Two groups of beagle dogs were used for in vivo studies. Group A were orally administered a single dose of GLS4 (15 mg/kg) with or without ketoconazole pretreatment (100 mg/d for 8 consecutive days). Group B were orally administered a single dose of GLS4 (15 mg/kg) with or without rifampicin pretreatment (100 mg/d for 8 consecutive days). Plasma was sampled after GLS4 dosing. GLS4 concentrations were determined by HPLC-tandem mass spectrometry. Results: The metabolic profile of [14 C]GLS4 in human and dog liver microsomes and CYP3A4 was similar. The major metabolites were morpholine N-dealkylated GLS4 and morpholine N,N-di-dealkylated GLS4. Pretreatment with ketoconazole or rifampicin significantly affected the plasma concentrations of GLS4 in dogs: ketoconazole increased the area under the concentration-time curve from 0 to infinity and peak concentration of GLS4 by 4.4 and 3.3 folds, respectively, whereas rifampicin decreased these parameters by 88.5% and 83.2%, respectively. Conclusion: GLS4 is a sensitive substrate of CYP3A. CYP3A inhibitors or inducers cause considerable change of GLS4 plasma concentrations in dogs, which should be considered in clinical practice.

A First-in-Human Trial of GLS4, a Novel Inhibitor of Hepatitis B Virus Capsid Assembly, following Single- and Multiple-Ascending-Oral-Dose Studies with or without Ritonavir in Healthy Adult Volunteers

“…In our study, more significant effects on the C min,ss , C max,ss , and AUC of GLS4 than on the t 1/2 were observed, indicating that the increase in oral bioavailability was mainly due to inhibited presystemic clearance. This was consistent with a study of the effect of ketoconazole on the pharmacokinetics of GLS4 in dogs, suggesting that the interaction between GLS4 and CYP3A modulators occurs in the duodenal wall (17).…”

“…Preliminary studies of GLS4 in dog and human liver microsomes indicate that GLS4 is a sensitive CYP3A substrate and that first-pass metabolism plays an important role in GLS4 elimination. The major metabolic pathway involved was N-dealkylation at the morpholine ring, which was mainly catalyzed by CYP3A4 (17). However, GLS4 displayed moderate CYP3A4 induction in a concentration-dependent manner in this study.…”

“…An in vitro recombinant enzyme test showed that CYP2C19, CYP3A4, and CYP3A5 are involved in GLS4 metabolism, and the main metabolic pathways are dealkylation, hydrolyzation, dehydrogenation, and oxidation. The types of metabolites in dog liver microsomes were the most similar to those in humans (17). All the metabolites show no activities against HBV in vitro assay.…”

CYP3A4 Mediates Oxidative Metabolism of the Synthetic Cannabinoid AKB-48

“…In addition, deliberate CYP inhibition is used as a therapeutic strategy for some HIV antivirals. This is the case for the lopinavir/ritonavir protease inhibitor cocktail, in which ritonavir boosts the plasma level of the active drug (lopinavir) by acting as a CYP3A4 inhibitor (35).…”

Recent Advance of the Hepatitis B Virus Inhibitors: A Medicinal Chemistry Overview

“…To build upon these findings, a series of BAY 41-4109 analogs were synthesized, and several analog compounds were endowed with potent antiviral activity in HepG2.2.15 cells. GLS4 (36) (Figure 8) was revealed to have more potent antiviral activity and less toxicity than BAY 41-4109 in HepG2.2.15 cells [91][92][93][94][95].…”