CYP3A4, Tacrolimus and kidney transplantation

Abstract

Introduction: Tacrolimus is an immunosuppressive drug widely used to prevent liver, kidney, lung and heart rejection after transplantation. Once absorbed, this drug is mainly metabolized and inactivated in the cells by two enzymes of the cytochrome P450 family, CYP3A4 and CYP3A5. Recent studies showed the presence of a SNP in intron 6 of the gene encoding for CYP3A4 where a C nucleotide in position rs35599367 is substituted by a T. This substitution leads to a decrease in the activity of CYP3A4. This allele was proven to be present in 5-7% in the Caucasian population. Experimental analysis: the purpose of this study is to give an idea about the frequency of the SNP in the Lebanese population, to compare it with the frequency in the Caucasian population, and to establish a correlation between this SNP and Tacrolimus metabolism based on Tacrolimus concentration in blood, taking into consideration weight and hemoglobin levels. 66 blood samples were collected from SGHUMC and Saint George laboratories. DNA was extracted from these samples, and genotyping for the CYP3A4 gene was performed using TaqMan probes on an ABI PRISM 7500 Fast Real Time PCR. Statistical analysis was performed to study the correlation between the genotypes and Tacrolimus metabolism. Results: The results showed that 10.6 % of the genotyped sample had a T genotype for the SNP rs35599367. The results of the formula average [tacro]/Daily Dose x weight showed a 1.7 fold increase from the C to the T genotype. The concentrations corresponding to 4 and 6mg respectively were 8.99 and 10.89 for C group and 13.83 and 16.38 for T group, thus a 1.5 fold increase between the groups was detected. Statistical analysis showed that the confounders had no effect on blood Tacrolimus concentrations. Conclusion: The frequency of this mutation in the Lebanese population is higher than in Caucasian population. Moreover, the substitution of the C nucleotide by T at position rs35599367 decreases Tacrolimus metabolism thus increases Tacrolimus concentration in blood.