Effects of FMO3 Polymorphisms on Pharmacokinetics of Sulindac in Chinese Healthy Male Volunteers.
Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3HHDD) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3hhdd) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of sulindac, sulindac sulfide, and sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium (D' = 0.977,r2= 0.944). The mean values ofCmax, AUC0-24, and AUC0-∞of sulindac were significantly higher in FMO3hhddgroup than those of FMO3HHDDgroup (P< 0.05), while the pharmacokinetic parameters exceptTmaxof sulindac sulfide and sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of sulindac in Chinese healthy male volunteers.
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China; Department of Pediatrics, Xiangya Hospital, Central South University, Changsha 410008, China.
Yong-Jun
YJ
Tang
Department of Neurology, Xiangya Hospital, Central South University, Changsha 410078, China.
Kai
K
Hu
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China; Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637, USA.
Wei-Hua
0000-0003-4167-8304
WH
Huang
Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637, USA.
Chong-Zhi
0000-0002-0950-2109
CZ
Wang
Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637, USA.
Zhi
Z
Liu
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
Yao
Y
Chen
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
Dong-Sheng
DS
Ouyang
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
Zhi-Rong
0000-0002-0420-6298
ZR
Tan
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.
Hong-Hao
HH
Zhou
Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637, USA.
Chun-Su
0000-0002-0711-2342
CS
Yuan
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005787:Gene Frequency; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D010105:Oxygenases / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D013467:Sulindac / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013467:Sulindac; C025462:sulindac sulfide; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C025463:sulindac sulfone