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Title: Significant Impact of Gene Polymorphisms on Tacrolimus But Not Cyclosporine Dosing in Asian Renal Transplant Recipients
Authors: Loh, PT
Lou, HX
Zhao, Y
Chin, YM
Vathsala, A 
Keywords: ATP Binding Cassette Transporter, Subfamily B, Member 1
Cytochrome P-450 CYP3A
Dose-Response Relationship, Drug
Drug Therapy, Combination
Immunosuppressive Agents
Kidney Transplantation
Middle Aged
Patient Selection
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Issue Date: 1-Jun-2008
Publisher: Elsevier BV
Citation: Loh, PT, Lou, HX, Zhao, Y, Chin, YM, Vathsala, A (2008-06-01). Significant Impact of Gene Polymorphisms on Tacrolimus But Not Cyclosporine Dosing in Asian Renal Transplant Recipients. Transplantation Proceedings 40 (5) : 1690-1695. ScholarBank@NUS Repository.
Abstract: Calcineurin inhibitors (CNI) are metabolized by cytochrome-P4503A (CYP3A) enzymes and extruded into the intestinal lumen by the drug efflux pump, P-glycoprotein (P-gp). The impact of single nucleotide polymorphisms (SNPs) of genes encoding CYP3A5 and P-gp on CNI dosing was examined among Asian renal transplant recipients. Frequencies of CYP3A5*1 versus *3 and MDR1-C3435T were correlated with tacrolimus (TAC) and cyclosporine (CSA) concentration-to-dose (C/D) ratios. Among 82 recipients (49% male; 88% Chinese), the majority were CYP3A5 expressors (*1*1 and *1*3, 11% and 40%, respectively) and 49% were nonexpressors (*3/*3). The prevalence of MDR-1-C3435T variants was 3435CC (41%), 3435CT (46%), and 3435TT (13%). Among 18 TAC-treated recipients, all receiving Diltiazem (DTZ), the median C/D ratio was lower for CYP3A5 *1/*1 versus *1/*3 versus *3/*3 (1.9, 4.6, and 13.5 ng/mL per 0.1 mg/kg/d, respectively; P = .001). The median C/D ratio was higher for TAC-treated patients with MDR-1-3435CC (14.1, 7.3, and 2.2 ng/mL per 0.1 mg/kg/d for CC, CT, and TT, respectively; P = .023). Neither CYP3A5 nor MDR-1-C3435T variants had an impact on CSA C/D ratios. Thus, CYP3A5 SNP has a significant impact on TAC dosing in Asian renal transplant recipients, which was likely to facilitate TAC metabolism. Although MDR-1-3435CC with higher P-gp expression should experience more TAC efflux and, therefore, lower TAC C/D ratios, all MDR-1-3435CC carriers were CYP3A5 nonexpressors; the latter ultimately contributed to the observed higher TAC C/D ratios in this population. This study advocates starting with a higher TAC dose for CYP3A5 expressors. Coadministration of DTZ may further optimize the TAC level through preferential P-gp binding and CYP3A4 inhibition. © 2008 Elsevier Inc. All rights reserved.
Source Title: Transplantation Proceedings
ISSN: 0041-1345
DOI: 10.1016/j.transproceed.2008.04.010
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