Effect of intestinal CYP3A5 on postoperative tacrolimus trough levels in living-donor liver transplant recipients

Abstract

It has been reported that hepatic and intestinal cytochrome P450 (CYP) 3A4, CYP3A5 and P-glycoprotein affect the pharmacokinetics of tacrolimus, and that these proteins are associated with the large inter-individual variation in the pharmacokinetics of this drug. We previously showed that the concentration/dose ratio of tacrolimus tended to be lower in recipients of living-donor liver transplantation (LDLT) with a CYP3A5*1/*1-carrying graft. However, the effect of intestinal CYP3A5 remains to be elucidated. In the present study, we examined the CYP3A5 genotype in both recipients and donors, and the effect of the recipients' polymorphism on the concentration/dose ratio of tacrolimus in patients after LDLT. The CYP3A5*3 allele frequency was 80% in recipients and 77% in donors. The intestinal CYP3A5 mRNA expression level was significantly associated with genotype. The tacrolimus concentration/dose ratio was lower in recipients with the CYP3A5*1/*1 and *1/*3 genotype (CYP3A5 expressors) compared to the CYP3A5*3/*3 genotype (non-expressors). Amongst the combination of CYP3A5 genotypes between the graft liver and the native intestine, CYP3A5 expressors in both the graft liver and the native intestine had the lowest concentration/dose ratio of tacrolimus during 35 days after LDLT. Patients with the intestinal CYP3A5*1 genotype tended to require a higher dose of tacrolimus compared to the other group with the same hepatic CYP3A5 genotype. These results indicate that intestinal CYP3A5, as well as hepatic CYP3A5, plays an important role in the first-pass effect of orally administered tacrolimus.

Effects of diltiazem on pharmacokinetics of tacrolimus in relation to CYP3A5 genotype status in renal recipients: from retrospective to prospective

“…29 CYP3A5*1 carrier state is associated with higher hepatic and intestinal CYP3A5 expression and activity, [30][31][32][33] thus in CYP3A5 expressers, more diltiazme N-demethylation metabolites are formed resulting in stronger inhibition of CYP3A activity, which might explain the finding of our study. In addition, in recent years, expression of CYP3A enzyme has been shown to be transcriptionally regulated by nuclear receptor pregnane X receptor (PXR).…”

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

“…Previously, we showed that the cytochrome P450 (CYP) CYP3A5*1 allele not only in the liver (donor genotype) but also in the small intestine (recipient genotype) achieved lower concentration/dose (C/D) ratio of tacrolimus than that with CYP3A5*3 (rs776746)/*3 homozygotes in living-donor liver transplant patients. [3][4][5][6] Recently, a new SNP in the CYP3A4 gene, CYP3A4*1G in intron 10, has been found in human lymphoblastoid cell lines from different ethnic groups and is the most common SNP in Japanese patients. 7,8) Miura et al 9) reported that dose-adjusted area under the concentration-time curve and trough level of tacrolimus in renal transplant patients with CYP3A4*1G/*1G was lower than those in patients with CYP3A4*1/*1.…”

“…The CYP3A5*3 was detected using the polymerase chain reaction (PCR)-restriction fragment length polymorphism method as described previously. 6) We genotyped the CYP3A4*1G using Taqman ® Drug Metabolism Assays (catalogue number: C_26201900_30, Applied Biosystems, Foster, California, U.S.A.). PCR was performed according to the manufacturer's instructions using StepOnePlus Real-Time PCR System (Applied Biosystems).…”

Benefits of minimizing immunosuppressive dosage according to cytochrome P450 3A5 genotype in liver transplant patients: findings from a single-center study

“…A significant difference in tacrolimus daily dose and C/D ratios has also been reported between recipients with the CYP3A5 6986GG allele and those with the CYP3A5 6986AG/AA allele within 6 months of transplantation (Provenzani et al, 2011). A previous study also found that the genetic polymorphism of intestinal CYP3A5 in liver transplant patients was an important factor affecting tacrolimus blood concentration (Uesugi et al, 2006).…”