Open AccessA Minimal Physiologically‐Based Pharmacokinetic Model for Tacrolimus in Living‐Donor Liver Transplantation: Perspectives Related to Liver Regeneration and the cytochrome P450 3A5 (CYP3A5) Genotype
Author(s) -
Itohara Kotaro,
Yano Ikuko,
Tsuzuki Tetsunori,
Uesugi Miwa,
Nakagawa Shunsaku,
Yonezawa Atsushi,
Okajima Hideaki,
Kaido Toshimi,
Uemoto Shinji,
Matsubara Kazuo
Publication year - 2019
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12420
Subject(s) - tacrolimus , pharmacokinetics , cyp3a5 , genotype , pharmacology , liver transplantation , bioavailability , transplantation , biology , medicine , genetics , gene
In adult patients after living‐donor liver transplantation, postoperative days and the cytochrome P450 3A5 (CYP3A5) genotype are known to affect tacrolimus pharmacokinetics. In this study, we constructed a physiologically‐based pharmacokinetic model adapted to the clinical data and evaluated the contribution of liver regeneration as well as hepatic and intestine CYP 3A5 genotypes on tacrolimus pharmacokinetics. As a result, liver function recovered immediately and affected the total body clearance of tacrolimus only during a limited period after living‐donor liver transplantation . The clearance was about 1.35‐fold higher in the recipients who had a liver with the CYP 3A5*1 allele than in those with the CYP 3A5*3/*3 genotype, whereas bioavailability was ~0.7‐fold higher in the recipients who had intestines with the CYP3A5*1 allele than those with CYP 3A5*3/*3 . In conclusion, the constructed physiologically‐based pharmacokinetic model clarified that the oral clearance of tacrolimus was affected by the CYP 3A5 genotypes in both the liver and intestine to the same extent.