Influence of CYP3A5 and ABCB1 Polymorphism on Tacrolimus Drug Dosing in South Indian Renal Allograft Recipients.

Abstract

Introduction:Tacrolimus blood levels are influenced by polymorphisms involving Cytochrome 3A subfamily (CYP3A5) and P-Glycoprotein (ABCB-1) genes. However, their role in transplant outcomes was less studied in South Indian population. We studied the prevalence and impact of these polymorphisms in renal transplant recipients from South India.Methods:An analysis of CYP3A5, ABCB1 genotype done in 101 renal transplant recipients by polymerase chain reaction was correlated with blood tacrolimus trough levels (CLIA method), weight, concentration/dose (L/D) ratio, incidence of biopsy proven early acute rejections, and tacrolimus toxicity.Results:Prevalence of CYP3A5*1/*1, *1/*3 and *3/*3 and ABCB1 (3435C>T) TT, CT, CC genotypes were 12 (11.9%), 48 (47.5%), 41 (40.6%) and 16 (15.8%), 45 (44.6%), 40 (39.6%), respectively. Mean tacrolimus level, median concentration/dose (L/D) ratio were significantly lower in homozygous (CYP3A5*1/*1-6.01 ng/mL; 48.99 ng/mL/mg/kg/day) and heterozygous expresser group (CYP3A5*1/*3-5.84 ng/mL; 68.93 ng/mL/mg/kg/day) when compared with nonexpresser group [CYP3A5*3/*3-7.46 ng/mL (P < 0.001);181.3 ng/mL/mg/kg/day (P < 0.05]. No significant differences observed between the ABCB1 genotypic groups. Incidence of early acute rejections (30% vs. 9.76%; P 0.016) and tacrolimus-related toxicity (14.6% vs. 5%; P 0.039) were significantly higher in CYP3A5 expressers and nonexpressers, respectively. No correlation observed between the ABCB1 polymorphisms between rejection episodes or tacrolimus renal toxicity. Among 101 patients, 40.6% were non-expressers (poor metabolizers) (*3/*3).Conclusions:CYP3A5 polymorphisms correlated with tacrolimus dose requirements and blood levels, incidence of early acute rejection, and tacrolimus nephrotoxicity. CYP3A5 polymorphism analysis prior to renal transplant will aid more precise early tacrolimus dose calculation to balance between rejection and toxicity.