Pharmacokinetics of Fluvoxamine in Relation to CYP2C19 Phenotype and Genotype

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Abstract
To evaluate the pharmacokinetics of fluvoxamine (FLV) in poor metabolizers (PMs) versus extensive metabolizers (EMs) of cytochrome P450 (CYP)2C19. This was a prospective, open-label study conducted at the Clinical Research Unit School of Pharmacy. Fifty-seven healthy, nonsmoking volunteers aged 21-40 years participated. Subjects abstained from caffeinated products 12 hours prior to and during each testing period. To assess CYP2C19 activity, blood samples were collected from each subject prior to and two hours after a single dose of omeprazole 20 mg. Once PMs were identified, a sample population of EMs were selected for comparison between the two groups regarding FLV disposition. A single 100 mg FLV dose was given to EMs and PMs; blood samples for FLV analysis were obtained prior to drug administration and 0.5, 1, 2, 3, 4 6, 8, 12 and 24 hours later. A blood sample one day prior to FLV administration was also obtained for CYP2C 19 and CYP2D6. Four PMs were identified with the omeprazole phenotype probe and had a mean +/- SD hydroxylation index of 1.335 +/- 0.271. Nine EMs were selected based upon a hydroxylation index between 0.100 and 0.400 (mean 0.193 +/- 0.079). FLV pharmacokinetic parameters (AUC, elimination half-life, Cmax and Tmax) did not significantly differ between the two groups. Genotype analysis for CYP2C19 revealed a mutant allele for the *2 which confirmed phenotype detection of PM status. Genotype analysis for CYP2D6*3 and *4 alleles showed that all PMs of CYP2C19 were EMs of FLV disposition and dosing is unlikely to be affected by CYP2C19 polymorphism.

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