Dmd062117 455..458

Tacrolimus requires close therapeutic drug monitoring because of its narrow therapeutic index and marked interindividual pharmacokinetic variation. In this study, we investigated the associations of polymorphisms in the gene encoding 11b-hydroxysteroid dehydrogenase type 1 (HSD11B1) with tacrolimus concentrations in Chinese renal transplant recipients during the early posttransplantation stage. A total of 258 renal transplant recipients receiving tacrolimus with prednisone (30 mg) combined therapy were genotyped for HSD11B1 rs846908, rs846910, rs4844880, andCYP3A5*3 polymorphisms. Tacrolimus trough concentrations were determined on days 6–9 after transplantation, measured by a chemiluminescent microparticle immunoassay. Among the CYP3A5 expressers, the dose-adjusted trough concentration (C0/D) of tacrolimus in HSD11B1 rs846908 AA homozygous individuals was considerably lower than found in GG+GA carriers [56.2 (23.9-86.6) versus 76.7 (12.6–220.0) (ng/ml)/(mg/kg), P = 0.0204]; HSD11B1 rs846910 AA homozygotes had a lower tacrolimus C0/D compared with GG+GA carriers [51.2 (23.9–86.6) versus 76.3 (12.6–220.0) (ng/ml)/(mg/kg), P = 0.0367]; carriers with the HSD11B1 rs4844880 AA genotype had a significantly lower tacrolimus C0/D with respect to carriers of TT+TA genotypes [61.3 (23.9–97.5) versus 77.2 (12.6–220.0) (ng/ml)/(mg/kg), P = 0.0002]; the HSD11B1 AA-AA-AA haplotype carriers had a lower tacrolimus C0/D than noncarriers [51.2 (23.9– 86.6) versus 76.3 (12.6–220.0) (ng/ml)/(mg/kg), P = 0.0367]. These findings illustrate that the HSD11B1 genotypes are closely correlated with tacrolimus trough concentrations, suggesting that these polymorphisms may be useful for safer dosing of tacrolimus.