The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients

Abstract

Cyclosporine and tacrolimus are immunosuppressive drugs largely used in renal transplantation. They are characterized by a wide inter-individual variability in their pharmacokinetics with a potential impact on their therapeutic efficacy or induced toxicity. CYP3A5 and P-glycoprotein appear as important determinants of the metabolism of these drugs. The objective of this study was to investigate the effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood concentrations in stable transplant patients. Stable renal transplant recipients receiving cyclosporine (n = 50) or tacrolimus (n = 50) were genotyped for CYP3A5*3 and *6, and MDR1 C1236T, G2677T/A and C3435T. Dose-adjusted trough blood levels (ng/ml per mg/kg body weight) as well as doses (mg/kg body weight) required to achieve target blood concentrations were compared among patients according to allelic status for CYP3A5 and MDR1. Dose-adjusted trough concentrations were three-fold and 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1/*3 patients for tacrolimus and cyclosporine, respectively. In the case of tacrolimus, the difference was even more striking when considering CYP3A5*1/*1 patients showing dose-adjusted trough concentrations 5.8-fold lower than CYP3A5*3/*3 patients. For both drugs, no association was found between trough blood concentrations or dose requirement and MDR1 genotype. Multiple regression analyses showed that CYP3A5*1/*3 polymorphism explained up to 45% of the variability in dose requirement in relation to tacrolimus use. Given the importance of rapidly achieving target blood concentrations after transplantation, further prospective studies should consider the immediate post-graft period and assess the influence of this specific polymorphism. Beside non-genetic factors (e.g. steroids dosing, drugs interactions), CYP3A5 pharmacogenetic testing performed just before transplantation could contribute to a better individualization of immunosuppressive therapy.

Diltiazem augments the influence of MDR1 genotype status on cyclosporine concentration in Chinese patients with renal transplantation

“…Dennis et al [18] reported that MDR1 C3435T did not influence the dose-adjusted trough blood concentration of CsA in stable renal transplant patients. Consistent results were obtained in another study involving American renal transplant patients [19] . Crettol et al [20] also reported that MDR1 genotypes did not influence the dose-adjusted trough blood concentration of CsA in transplant recipients.…”

“…In recent years, high inter-individual heterogeneity in the MDR1 gene, influencing the metabolism of digoxin [15][16][17] , cyclosporin [18][19][20] , tacrolimus [21][22][23] and amlodipine [24] , has been described. In the present study, we explored the association of MDR1 SNPs with CsA dose requirements and adjusted concentration in renal recipients co-treated or not with diltiazem.…”

The effect of CYP3A5 polymorphism on dose-adjusted cyclosporine concentration in renal transplant recipients: a meta-analysis

“…There were four studies that did not show the concentrations of *1/*1 and *1/*3 genotypes separately. 16,23,26 In addition, in the study of Haufroid et al, 21 there was no subject with *1/*1 genotype. Among all the subjects, the frequencies of CYP3A5*1/*1 þ *1/*3 (expresser) and *3/*3 (non-expresser) were 34.73 and 65.27%, respectively.…”

“…Five studies were from western countries, including France, the Netherlands, Belgium, United States and Germany, 14,16,[20][21][22] whereas 9 were from Asian countries, of which 6 were from China, [11][12][13][23][24][25] and the remaining 3 were performed in India, Singapore and Malaysia, respectively. [26][27][28] Most of the CsA administrations were multiple oral doses adjusted according to C 0 or C 2 levels.…”

Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients

“…As these genes have functional polymorphisms affecting drug metabolism, there have been many pharmacogenetics studies. [4][5][6][7][8][9] Because this type of study helps us predict the patient's biological response to a drug, we can avoid the side effects and provide suitable therapy for each individual.…”