The Effect Of CYP3A4, CYP3A5 AND CYP2D6 On Tacrolimus Metabolism In Renal Transplantation Patients

Objective:To investigate the effect of cytochrome P450(CYP) CYP3A4, CYP3A5 and C3YP2D6 single nucleotide polymorphism(SNP) on Tacrolimus (Tac) pharmacokinetics and study the feasibility of personalized base treatment of Tacrolimus.Methods:From 2013-8 to 2013-12138 post renal-transplant patient on Tacrolimus and with stable graft function were followed up in our hospital. Drug dose as per body weight was recorded, the trough concentration of Tacrolimus was calculated and gene sequencing was used to detect single nucleotide polymorphism of CYP (450) 3A4,3A4 and 2D6. The dose normalized concentration of Tacrolimus and its relationship with SNP was analyzed.Results:The 138 patient profiles provide the relation of Tacrolimus dose with the CYP gene. Among 138 patients genotyped for CYP3A4,137 case displayed the wild type (49 female and 88 male). One male mutant case was recorded. CYP3A5 distribution pattern revealed 71 wild type (27 female,46 male),55 case of mutant heterozygous (20 female,35 male) and 10 cases of mutant homozygous (2 female,8 male) respectively. Similarly the distribution pattern for CYP2D6 showed 73 case of wild type (28 female,45male),34 case of heterozygous mutant (11 female,23 male) and 31 cases of homozygous mutant (10 female,21 male). The three different type of genotype and population distribution as per gender did not reach statically significant. Compared to mutant heterozygous and homozygous allele, wild type CYP3A5 expressers require higher Tacrolimus dose (p=0.002, p=0.039), but between the two mutant allele no statically significance was observed. Wild type and mutant heterozygous compared with homozygous allele, wild type and mutant heterozygous of CYP2D6 require higher Tacrolimus dose (p=0.003, p=0.029).The comparison of wild type and mutant homozygous did not reach statically significant.Conclusions:1. The CYP3A4 genotype polymorphism rate was very low and the significance of this gene in Tacrolimus metabolism is minimal in Chinese population.2. CYP3A5 has a major role in Tacrolimus metabolism and the wild type need more dose of tacrolimus.3. Polymorphism of CYP2D6 gene has a certain role in Tacrolimus metabolism, and wild type expresser need higher dose of Tacrolimus, but its effect is lower than CYP3A5. CYP2D6 may play a leading role in Tacrolimus metabolism when CYP3A5 is heterozygous allele.