TY - JOUR
T1 - A Minimal Physiologically-Based Pharmacokinetic Model for Tacrolimus in Living-Donor Liver Transplantation
T2 - Perspectives Related to Liver Regeneration and the cytochrome P450 3A5 (CYP3A5) Genotype
AU - Itohara, Kotaro
AU - Yano, Ikuko
AU - Tsuzuki, Tetsunori
AU - Uesugi, Miwa
AU - Nakagawa, Shunsaku
AU - Yonezawa, Atsushi
AU - Okajima, Hideaki
AU - Kaido, Toshimi
AU - Uemoto, Shinji
AU - Matsubara, Kazuo
N1 - Funding Information:
Funding. This study was supported in part by Grant-in Aid for the Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS) Grant numbers 16K08400 and 18H00394.
Publisher Copyright:
© 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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U2 - 10.1002/psp4.12420
DO - 10.1002/psp4.12420
M3 - Article
C2 - 31087501
AN - SCOPUS:85067414269
SN - 2163-8306
VL - 8
SP - 587
EP - 595
JO - CPT: Pharmacometrics and Systems Pharmacology
JF - CPT: Pharmacometrics and Systems Pharmacology
IS - 8
ER -