Influence of Cytochrome P450 (CYP) <i>3A4*1G</i> Polymorphism on the Pharmacokinetics of Tacrolimus, Probability of Acute Cellular Rejection, and mRNA Expression Level of CYP3A5 Rather than CYP3A4 in Living-Donor Liver Transplant Patients

Abstract

Association between cytochrome P450 (CYP) 3A4*1G genotype of donors (n 412) and/or recipients (n 410), and the pharmacokinetics of tacrolimus and the risk of acute cellular rejection was examined in Japanese living-donor liver transplant patients between 2004 and 2011. The concentration/dose (C/D) ratio of tacrolimus in patients carrying graft liver with CYP3A4*1/*1 was significantly higher during 7 d after surgery than in that with CYP3A4*1/*1G (214 vs. 157 [ng/mL]/[mg/kg/day], p<0.01). After postoperative day 8, no significant difference was observed among CYP3A4*1G genotypes in the graft liver. However, the C/D ratio in CYP3A4*1/*1 of the intestine was significantly higher than that in CYP3A4*1G/*1G for 5 weeks after surgery (postoperative days 1-14; p<0.001, postoperative days 15-35; p<0.01). During postoperative days 14 and 26, acute cellular rejection incidences tended to be lower in the patients with graft liver carrying the CYP3A4*1/*1 allele than in the patients carrying CYP3A4*1G allele (8.7% vs. 14.6%, p 0.0973). However, CYP3A4*1G in the intestine had almost no effect on the incidence of rejection (9.9% in CYP3A4*1/*1 vs. 12.5% in CYP3A4*1G allele, p 0.4824). CYP3A4*1G was significantly related to mRNA expression of CYP3A5 rather than of CYP3A4 in the graft liver and intestine and was strongly linked with the CYP3A5*1. Thus, we elucidated that CYP3A4*1G genotype in the intestine was an important indicator of the pharmacokinetics of tacrolimus, whereas this genotype in the graft liver tended to influence the frequency of acute cellular rejection after transplantation.

Personalized Tacrolimus Dose Requirement by CYP3A5 but Not ABCB1 or ACE Genotyping in Both Recipient and Donor after Pediatric Liver Transplantation

“…Other genetic variants may explain additional variation in TAC dose requirement. As has been illustrated in adults, the drug transporter ABCB1, the CYP3A4, the human pregnane X receptor (NR1I2), interleukin 6 and COMT SNP may be associated with early TAC exposure [9] , [24] – [26] . Although the association of ABCB1 , ACE with the C/D ratios of TAC was investigated, we didn’t observe any significant impact on TAC disposition in pediatric liver transplants ( Fig.…”

The correlation between the expression of genes involved in drug metabolism and the blood level of tacrolimus in liver transplant receipts

“…It has been reported that CYP3A4*1G genotype in the graft liver contributes to the frequency of acute cellular rejection after transplantation 40 . Based on this evidence, we speculate that the expression profile of genes involved in drug metabolism in the graft liver, including CYP genes and genes studied in our work, may have impact on pharmacokinetics of drugs in liver transplant receipts.…”

Functional Gene Variants of CYP3A4

“…LD was also observed in a clinical study investigating the influence of the CYP3A4*1G polymorphism on tacrolimus pharmacokinetics and CYP3A5 mRNA expression levels in 421 Japanese liver transplant patients. 35 The LD possibly explains some observations on the uncertain functional significance of this CYP3A4 variant. 9,34,35…”

“…35 The LD possibly explains some observations on the uncertain functional significance of this CYP3A4 variant. 9,34,35…”