Abstract
Teneligliptin, a dipeptidyl peptidase-4 inhibitor, is used to treat type 2 diabetes mellitus. FMO3 and CYP3A4 metabolize teneligliptin into teneligliptin sulfoxide. This study examined the effects of FMO3 (rs909530, rs1800822, rs2266780, and rs2266782) and CYP3A4 (rs2242480) polymorphisms on teneligliptin pharmacokinetics at a steady state among 23 healthy participants administered 20 mg teneligliptin daily for 6 days. Subjects with FMO3 rs909530, rs2266780, and rs2266782 polymorphisms exhibited a significant gene dosage-dependent increase in maximum steady-state plasma drug concentration (Cmax,ss) and area under the drug concentration vs time curve (AUC) (p<0.05). However, the Cmax values significantly decreased but the AUC values did not significantly vary in subjects with CYP3A4 polymorphism (rs2242480). These results suggest that FMO3 and CYP3A4 polymorphisms affect teneligliptin pharmacokinetics in humans. The findings of this study provide a scientific basis for the inter-individual variation in teneligliptin disposition.
Highlights
Teneligliptin, which belongs to the family of dipeptidyl peptidase-4 inhibitors, is used to treat type 2 diabetes mellitus (T2DM)
This study aimed to examine the potential effects of Flavin-containing monooxygenase 3 (FMO3) and cytochrome P450 3A4 (CYP3A4) polymorphisms on teneligliptin pharmacokinetics in humans
This study demonstrated that the rs909530, rs2266780, and rs2266782 polymorphisms of FMO3 and the rs2242480 polymorphism of CYP3A4 affected the pharmacokinetics of teneligliptin in humans
Summary
Teneligliptin, which belongs to the family of dipeptidyl peptidase-4 inhibitors, is used to treat type 2 diabetes mellitus (T2DM). Flavin-containing monooxygenase 3 (FMO3) and cytochrome P450 3A4 (CYP3A4) are involved in teneligliptin metabolism in the liver (3). Previous clinical and in vitro studies have elucidated the mechanism of teneligliptin metabolism using various inhibitors of FMO3 and CYP3A4, such as ketoconazole and methimazole (5,6). Ketoconazole and methimazole (FMO inhibitor) inhibit teneligliptin metabolism by 47.0 and 67.2%, respectively, in the human microsomes (7). FMO3 polymorphisms, including rs909530 (c.855C>T, N285N), rs2266782 (c.472G>A, E158K), and rs2266780 (c.923A>G, E308G), are reported to affect the pharmacokinetic characteristics of sulindac, a FMO3 substrate (8,9). Rs2242480 (g.20230G>A, IVS10 + G12A, and CYP3A4*1G) located in intron 10 is one of the most frequent genetic polymorphisms in the East Asian population and affects the pharmacokinetic characteristics of various drugs by up-regulating (13) or downregulating CYP3A4 activity (14,15).
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