title: A semi-physiologically-based pharmacokinetic model characterizing mechanism-based auto-inhibition to predict stereoselective pharmacokinetics of verapamil and its metabolite norverapamil in human.
abstract: Verapamil and its major metabolite norverapamil were identified to be both mechanism-based inhibitors and substrates of CYP3A and reported to have non-linear pharmacokinetics in clinic. Metabolic clearances of verapamil and norverapmil as well as their effects on CYP3A activity were firstly measured in pooled human liver microsomes. The results showed that S-isomers were more preferential to be metabolized than R-isomers for both verapamil and norverapamil, and their inhibitory effects on CYP3A activity were also stereoselective with S-isomers more potent than R-isomers. A semi-physiologically based pharmacokinetic model (semi-PBPK) characterizing mechanism-based auto-inhibition was developed to predict the stereoselective pharmacokinetic profiles of verapamil and norverapamil following single or multiple oral doses. Good simulation was obtained, which indicated that the developed semi-PBPK model can simultaneously predict pharmacokinetic profiles of S-verapamil, R-verapamil, S-norverapamil and R-norverapamil. Contributions of auto-inhibition to verapamil and norverapamil accumulation were also investigated following the 38th oral dose of verapamil sustained-release tablet (240mg once daily). The predicted accumulation ratio was about 1.3-1.5 fold, which was close to the observed data of 1.4-2.1-fold. Finally, the developed semi-PBPK model was further applied to predict drug-drug interactions (DDI) between verapamil and other three CYP3A substrates including midazolam, simvastatin, and cyclosporine A. Successful prediction was also obtained, which indicated that the developed semi-PBPK model incorporating auto-inhibition also showed great advantage on DDI prediction with CYP3A substrates.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China; Department of Drug Metabolism and Pharmacokinetics, Hutchison Medipharma Ltd., Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Sumei
authors.initials: S
authors.lastname: Xia
authors.forename: Weifang
authors.initials: W
authors.lastname: Xue
authors.forename: Dawei
authors.initials: D
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Sai
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
mesh_terms: D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D008954:Models, Biological; D019821:Simvastatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D013237:Stereoisomerism; D014700:Verapamil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D002121:Calcium Channel Blockers; D016572:Cyclosporine; C016904:norverapamil; D019821:Simvastatin; D014700:Verapamil; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam
keywords: Auto-inhibition; CYP3A; Drug–drug interaction; Semi-physiologically-based pharmacokinetic model; Stereoselective pharmacokinetics; Verapamil