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Toxicol Lett. 2015 Jan 22;232(2):458-65. doi: 10.1016/j.toxlet.2014.11.018. Epub 2014 Nov 20.

In vitro selective inhibition of human UDP-glucuronosyltransferase (UGT) 1A4 by finasteride, and prediction of in vivo drug-drug interactions.

Author information

1
College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 420-743, Republic of Korea.
2
College of Pharmacy and BK21 PLUS R-FIND Team, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang, Gyeonggi-do 410-820, Republic of Korea.
3
College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 420-743, Republic of Korea. Electronic address: baesk@catholic.ac.kr.

Abstract

In the present study, we evaluated the inhibitory potentials of finasteride for the major human hepatic UDP-glucuronosyltransferases (UGTs) (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15) in vitro using LC-MS/MS by specific marker reactions in human liver microsomes (except for UGT2B15) or recombinant supersomes (UGT2B15). Of the seven tested UGTs, finasteride potently, selectively, and competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation in human liver microsomes with an IC₅₀ value of 11.5 ± 1.78 μM and Ki value of 6.03 ± 0.291 μM. This inhibitory potency was similar to that of hecogenin, a well-known inhibitor of UGT1A4. However, finasteride did not seem to inhibit any of the other six UGTs: UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7, or UGT2B15. Similarly, finasteride markedly inhibited UGT1A4 activity in recombinant human UGT1A4 supersomes, with a Ki value of 6.05 ± 0.410 μM. In addition, finasteride strongly inhibited UGT1A4-catalyzed imipramine-N-β-D-glucuronidation. However, on the basis of an in vitro-in vivo extrapolation, our data strongly suggested that finasteride is unlikely to cause clinically significant drug-drug interactions mediated via inhibition of the hepatic UGT enzymes involved in drug metabolism in vivo.

KEYWORDS:

Finasteride; In vitro; In vivo prediction; UGT inhibition

PMID:
25448279
DOI:
10.1016/j.toxlet.2014.11.018
[Indexed for MEDLINE]

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