A Minimal Physiologically-Based Pharmacokinetic Model for Tacrolimus in Living-Donor Liver Transplantation: Perspectives Related to Liver Regeneration and the cytochrome P450 3A5 (CYP3A5) Genotype

Kotaro Itohara, Ikuko Yano, Tetsunori Tsuzuki, Miwa Uesugi, Shunsaku Nakagawa, Atsushi Yonezawa, Hideaki Okajima, Toshimi Kaido, Shinji Uemoto, Kazuo Matsubara

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

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 CYP3A5 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 CYP3A5*1 allele than in those with the CYP3A5*3/*3 genotype, whereas bioavailability was ~0.7-fold higher in the recipients who had intestines with the CYP3A5*1 allele than those with CYP3A5*3/*3. In conclusion, the constructed physiologically-based pharmacokinetic model clarified that the oral clearance of tacrolimus was affected by the CYP3A5 genotypes in both the liver and intestine to the same extent.

Original languageEnglish
Pages (from-to)587-595
Number of pages9
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume8
Issue number8
DOIs
Publication statusPublished - 2019
Externally publishedYes

ASJC Scopus subject areas

  • Modelling and Simulation
  • Pharmacology (medical)

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