![[ Visit Client Website ]](images/banner.gif)
Purpose: The pharmacokinetics of sulindac exhibits a wide inter-individual variability that may lead to poor predictability of treatment-related outcomes and side effects. This study aimed to investigate the effects of polymorphisms of sulindac-metabolizing enzymes on the pharmacokinetics of sulindac and its two metabolites, sulfide and sulfone, in patients with preterm labors.
Methods: Eleven single nucleotide polymorphisms (SNPs) of 3 genes, flavin-containing monooxygenase 3 (FMO3), methionine reductase A (MSRA), and aldehyde oxygenase 1 (AOX1), were genotyped, and plasma sulindac and its metabolite concentrations of 19 patients were measured at 0, 1.5, 4, and 10 hr after drug administration. The area under the curve from time 0 to the last sampling time point (AUClast) for sulindac, sulfide, and sulfone were obtained, and the ratios among sulindac and its metabolites were calculated. The production rate constant (kp) was calculated by the residual method.
Results: The AUClast ratio of sulfide to sulfone in patients with wild-type alleles or heterozygotes was less than half compared to those with variant homozygotes of FMO3 (rs909530). In contrast, patients with wild-type homozygotes or heterozygotes of the MSRA gene (rs9329221) resulted in an almost two-fold higher AUClast ratio of sulfide to sulfone compared to those with variant-type homozygotes. In terms of sulfide production, all patients with variant-type homozygotes in the FMO3 gene (rs909530) were fast producers (kp≥5 hr-1) whereas all patients with wild-type homozygotes or heterozygotes in the MSRA gene (rs9329221) were slow producers (kp<5 hr-1).
Conclusion: Differences of bioavailability ratios among sulindac and its metabolites are attributable to the genetic polymorphisms of FMO3 and MSRA in subjects with preterm labors. The results of this study could give some preliminary data to predict efficacies and side effects of sulindac for developing individualized treatment for patients with preterm labors.