Effects of Single-Nucleotide Polymorphisms of FMO3 and FMO6 Genes on Pharmacokinetic Characteristics of Sulindac Sulfide in Premature Labor

Abstract

This study aimed to investigate the effects of polymorphisms of the flavin-containing mono-oxygenase 3 (FMO3) and flavin-containing mono-oxygenase 6 (FMO6) genes on the pharmacokinetics of sulindac sulfide, the active metabolite of sulindac, in patients with preterm labor. Ten single-nucleotide polymorphisms (SNPs) were genotyped, and plasma sulindac sulfide concentrations were measured at 0, 1.5, 4, and 10 hours after drug administration. The area under the curve from time 0 to the last sampling time point (AUC last ) for sulindac sulfide was obtained. The AUC last of sulindac sulfide was significantly higher in patients with variant-type homozygotes of FMO3 (rs909530) than those with ancestral alleles or heterozygotes. FMO3 (rs2266780) was in complete linkage disequilibrium with FMO6 (rs7885012), and there was marginal significance between the genotypes (P = 0.049). From multiple linear regression models, FMO3 (rs909530) was found to have significant influence on the AUC last of sulindac sulfide after adjusting for gestational age, weight, and all studied SNPs. The predictive contribution of rs909530 to the variability of sulindac sulfide AUC last was 27.0%. In conclusion, the results of this study could help clinicians predict the efficacies and side effects of sulindac in the development of individualized treatment of patients with preterm labor. IntroductionSulindac is a prostaglandin synthetase inhibitor (Nuki, 1983). As prostaglandin increase is observed in both term and preterm labor, prostaglandin inhibitors have been used as tocolytic agents (Karim, 1968). Sulindac contains a chiral sulfoxide moiety and is administered clinically as a racemate. It is an inactive prodrug and is reduced to a pharmacologically active metabolite, sulindac sulfide. Sulindac is also oxidized to an inactive metabolite, sulindac sulfone. The sulfide form is inactivated by flavin-containing mono-oxygenase 3 (FMO3), and the (S)-and (R)-sulindac sulfoxides are also oxidized to sulindac sulfone by FMO3 (Hamman et al., 2000;Hisamuddin and Yang, 2007).Several studies showed that FMO3 gene polymorphisms could result in interindividual and interethnic differences in FMO3 activity (Cashman and Zhang, 2002;Hernandez et al., 2003). The polymorphisms could result in differences in the pharmacokinetics and responses of drugs that are metabolized by FMO3, including sulindac. It was reported that genetic polymorphisms of FMO3 could affect clinical outcomes in patients with sulindac therapy due to adenomatous polypsis. The studied end points were pharmacodynamic responses such as polyposis prevention and regression (Hisamuddin et al., 2004(Hisamuddin et al., , 2005. However, there has been no study conducted on the effects of FMO3 genotypes on the blood concentrations of an active sulindac metabolite in clinical settings.It has been reported that flavin-containing mono-oxygenase 6 (FMO6) has significant sequence homology with FMO3 Hernandez et al., 2004;Hisamuddin and Yang, 2007). However, unlike FMO3, the study of the effects of FMO6...

Targeted sequencing identifies genetic polymorphisms of flavin‐containing monooxygenase genes contributing to susceptibility of nicotine dependence in European American and African American

“…FMO6P is reported to have significant sequence homology with FMO3 (Hines et al., ). Previous studies have set up direct links of SNPs in FMO6P with chronic allograft dysfunction (Israni et al., ) and pharmacokinetic characteristics of sulindac sulfide in premature labor (Park et al., ). One interesting note for these previous studies is that the significant findings of FMO6P are always accompanied with significant findings from FMO3 , and at least in one study (Israni et al., ), the significant SNP of FMO6P is in complete LD with significant SNP of FMO3 .…”

Marketed nonsteroidal anti-inflammatory agents, antihypertensives, and human immunodeficiency virus protease inhibitors: as-yet-unused weapons of the oncologists’ arsenal

“… 16 , 19 , 20 In addition, such NSAIDs as aspirin and sulindac find application in the prevention of thrombosis and preeclampsia 21 , 22 or as antipyretic and tocolytic agents. 23 , 24 This further emphasizes the versatility of NSAIDs as therapeutics aside their potency as antitumor drugs, as presented in the following section.…”

Rapid Pyrosequencing Method for FMO3 Non-Synonymous Genetic Variant Evaluation in A Korean Population

“…The FMO3 gene contains nine exons ranging from 80 to 705 bp [7], and seven non-synonymous and two synonymous genetic polymorphisms have been identi ed [8]. Among them, FMO3 c.855C > T (rs909530), c.441C > T (rs1800822), c.923A > G (rs2266780), and c.472G > A (rs2266782) are known to be common in East Asian populations [9][10][11][12]. These mutations have shown frequent functional inter-individual and inter-ethnic variability, and their signi cance is associated with the pharmacokinetics of certain chemicals (e.g., sulindac and ranitidine) [9].…”

“…Moreover, increased levels of TMAO are associated with greater risk of cardiovascular disorders because they affect atherosclerosis pathogenesis [17]. Recently, it was reported that a mutation in FMO3 was responsible for sulindac pharmacokinetics in Korean and Chinese populations [9,18]. Because the pharmacogenetics of the FMO3 gene play a crucial role in its substrate disposition, it is necessary to develop a feasible method to detect SNPs and validate the analysis for future research.…”

“…Therefore, this study aimed to develop a rapid, feasible pyrosequencing method to detect nonsynonymous FMO3 SNPs c.855C > T (rs909530), c.441C > T (rs1800822), c.923A > G (rs2266780), and c.472G > A (rs2266782), all of which have been reported to be functional and commonly present in the Korean population [9,18], and compare allele frequencies with those reported in other ethnic groups.…”