Tacrolimus Dosing in Pediatric Heart Transplant Patients is Related to CYP3A5 and MDR1 Gene Polymorphisms

Abstract

Tacrolimus is a substrate for P-glycoprotein (P-gp) and cytochrome (CYP) P4503A. P-gp is encoded by the multiple drug resistance gene MDR1 and CYP3A is the major enzyme responsible for tacrolimus metabolism. Both MDR1 and CYP3A5 genes have multiple single nucleotide polymorphisms. The objective of this study was to evaluate whether the MDR1 exon21 and exon26 polymorphisms and the CYP3A5 polymorphism are associated with tacrolimus disposition in pediatric heart transplant patients. At 3, 6 and 12 months post transplantation, a significant difference in tacrolimus blood level per dose/kg/day was found between the CYP3A5 *1/*3 (CYP3A5 expressor) vs. *3/*3 (nonexpressor) genotypes with the *1/*3 patients requiring a larger tacrolimus dose to maintain the same blood concentration. There were no significant differences in tacrolimus blood level per dose/kg/day between MDR1 exon21 G2677T and exon 26 C3435T at 3 months, but both were found to have a significant association with tacrolimus blood level per dose/kg/day at 6 and 12 months. We conclude that specific genotypes of MDR1 and CYP3A5 in pediatric heart transplant patients require larger tacrolimus doses to maintain their tacrolimus blood concentration, and that this information could be used prospectively to manage patient's immunosuppressive therapy.

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

“…The contribution of MDR1 genetic polymorphisms has also been extensively studied for the calcineurin inhibitors cyclosporine and tacrolimus, which show large interindividual differences in oral bioavailability. Though two studies in renal transplant patients found cyclosporine and tacrolimus dose requirement to be higher in individuals homozygous for the 3435T allele (44,45), two other studies investigating tacrolimus steady-state dose requirement found an opposite effect, with plasma levels being lower in the 3435CC group after 3, 6, and 12 months (46,47). A recent study investigating the effect of genetic polymorphisms in CYP3A4, CYP3A5, and MDR1 on the pharmacokinetics of cyclosporine and tacrolimus also found no evidence supporting a role for the MDR1 C3435T polymorphism in dose requirement of the two drugs, consistent with previous reports regarding cyclosporin A trough levels and MDR1 genotype (48,49).…”

“…No difference in cyclosporine and tacrolimus dose requirement [49] Renal transplant patients T-129C, C1236T, G2677T/A (Ala893Ser/Thr), C3435T Tacrolimus Higher tacrolimus dose requirement in carriers of the 2677T/A alleles [44] Pediatric heart transplant patients G2677T/A (Ala893Ser/Thr), C3435T Tacrolimus Higher tacrolimus blood levels at 6 and 12 months [47] Japanese women T-129C -Increased placental P-glycoprotein expression levels [22] Caucasian volunteers C1236T + G2677T/A (Ala893Ser/Thr) + C3435T…”

Influence of Cytochrome P450 (CYP) <i>3A4*1G</i> Polymorphism on the Pharmacokinetics of Tacrolimus, Probability of Acute Cellular Rejection, and mRNA Expression Level of CYP3A5 Rather than CYP3A4 in Living-Donor Liver Transplant Patients

“…3,6) The CYP3A5*3 genotype is well-known to be associated with the pharmacokinetics of tacrolimus in patients with liver, kidney and heart transplant. [17][18][19][20] Hepatic and intestinal CYP3A5 plays a significant role in the clearance of tacrolimus after oral administration in liver transplant patients. 4,5) However, a newly identified SNP in the CYP3A4 gene, CYP3A4*1G affects the pharmacokinetics of some drugs.…”

Design of Allele Specific PCR for Rapid Detection of CYP3A5 (A6986G) and Mdr-1 (C3435T) Polymorphisms

“…Several studies have shown that the dose of tacrolimus is associated with CYP3A5 A6986G SNP [5][6][7]. Dose adjusted trough concentrations were 3 fold and 1.6 fold higher in mutants (G/G) than in heterozygous (A/G) patients for tacrolimus and Cyclosporine, respectively [8,9].…”