Significant impact of gene polymorphisms on tacrolimus but not cyclosporine dosing in Asian renal transplant recipients.
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.
Loh
P T
PT
Department of Renal Medicine, Singapore General Hospital, Singapore.
Lou
H X
HX
Zhao
Y
Y
Chin
Y M
YM
Vathsala
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D001208:Asia / Q000208:ethnology; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus