Prediction of CYP-mediated silybin A-losartan pharmacokinetic  interactions using physiological based pharmacokinetic modeling

This study aimed to assess silybin A-losartan interaction in different CYP2C9 genotypes using physiological-based pharmacokinetic (PBPK) model approach. The individual PBPK models for silybin A and losartan were developed using PK-Sim ®. Losartan pharmacokinetics was predicted with or without co-administration of silybin A in individuals of different CYP2C9 genotypes to find herbal-drug interaction. The predicted drug plasma curves and pharmacokinetic parameters were optimized using parameter identification tool and were compare d with reported pharmacokinetic parameters from the published clinical studies for model validation. The silybin-losartan interactions were predicted by change in area under the curve (AUC) and peak systemic concentration (Cmax). The co-treatment of silybin A, 420  mg/24 h (140 mg/8 h) with losartan 50 mg/24 h, exhibited a genotype-dependent change in the losartan’s AUC and Cmax. In CYP 2C9*1/*1 genotype, AUC and Cmax of losartan were increased 1.16 and 1.37 folds, respectively falling in a range stipulated for negligible interaction. Increase in AUC and Cmax by 0.873 and 0.294 folds, respectively inCYP2C9*1/*3 after co-administration of silybin A exhibited a minor interaction with losartan. However, in individuals withCYP2C9*1/*2 genotype, the losartan ’s AUC and Cmax were decreased by 0.01 folds, manifesting a moderate interaction. Hence, inCYP2C9*1/*1 andCYP2C9*1/*3 genotypes, silybin A is a weak CYP inhibitor for losartan while inCYP2C9...

Source: Journal of Pharmacokinetics and Pharmacodynamics - January 21, 2022 Category: Drugs & Pharmacology Source Type: research