¹Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital, and Department of Transplantation and Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Correspondence: Ken-ichi Inui, PhD, Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: inui@kuhp.kyoto-u.ac.jp

^*This work was supported in part by the 21st Century Center of Excellence Program "Knowledge Information Infrastructure for Genome Science"; by a grant-in-aid from the Japan Health Sciences Foundation ("Research on Health Sciences Focusing on Drug Innovation"); by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and by a grant-in-aid from the Japan Research Foundation for Clinical Pharmacology. Masahide Fukudo is a Research Fellow of the Japan Society for the Promotion of Science.

Received 13 February 2006; Accepted 13 June 2006.

Abstract

Objective: Our objective was to investigate the population pharmacokinetics of tacrolimus in pediatric living-donor liver transplant recipients and examine the effects of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes CYP3A4 and CYP3A5 on the oral clearance of tacrolimus.

Methods: Data were collected retrospectively from 130 de novo pediatric liver transplant recipients treated with tacrolimus during the first 50 postoperative days. Pharmacogenomic data including both the CYP3A5^*3 polymorphism and messenger ribonucleic acid (mRNA) expression levels of MDR1, CYP3A4, and CYP3A5 in the native intestine and the graft liver at transplantation were obtained from 65 of the recipients. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modeling program NONMEM to estimate population mean parameters of apparent clearance (CL/F) and apparent volume of distribution (V/F).

Results: Both CL/F and V/F were allometrically related to body weight, and CL/F decreased when the AST value was elevated. CL/F increased linearly in the immediate postoperative period but did not change with time after postoperative day 21. The intestinal MDR1 mRNA level significantly influenced the initial CL/F (P < .005). Furthermore, the increase in CL/F over time was 2 times higher (95% confidence interval, 1.19-2.81 times; P < .005) in recipients of a CYP3A5^*1-carrying graft liver than in patients with the hepatic CYP3A5^*3/^*3 genotype. The Bayesian prediction for tacrolimus concentrations was not significantly biased on any postoperative day, and the mean absolute prediction error was lower than 3 ng/mL after the first 2 weeks of transplantation.

Conclusions: The enterocyte MDR1 mRNA level and the CYP3A5^*1 allele in the graft liver contribute differently to the interindividual variability in the oral clearance of tacrolimus after living-donor liver transplantation.