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Open AccessArticle

In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole

1
College of Pharmacy, Pusan National University, Busan 46241, Korea
2
Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam 58554, Korea
3
Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea
4
Department of Physiology, College of Korean Medicine, Dongeui University, Busan 47227, Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Pharmaceutics 2019, 11(12), 673; https://doi.org/10.3390/pharmaceutics11120673
Received: 3 November 2019 / Revised: 30 November 2019 / Accepted: 9 December 2019 / Published: 11 December 2019
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Dutasteride (DUT) is a selective, potent, competitive, and irreversible inhibitor of both type-1 and type-2 5α-reductase (5AR) commonly used in the treatment of benign prostatic hyperplasia and androgenetic alopecia. In the present study, we developed a simple and sensitive high-performance liquid chromatography with fluorescence detection (HPLC-FL) method for simultaneous determination of DUT and its major active metabolite, 6β-hydroxydutasteride (H-DUT). Next, the pharmacokinetic interactions of DUT with ketoconazole (KET), a potent CYP3A inhibitor, were comprehensively investigated. In vivo rat intravenous and oral studies revealed that the pharmacokinetics of DUT and H-DUT were significantly altered by the co-administration of KET. Furthermore, the in vitro microsomal metabolism, blood distribution, and protein-binding studies suggest that the altered pharmacokinetics of DUT could be attributed primarily to the inhibition of the DUT metabolism by KET. To the best of our knowledge, this is the first study to show the drug interaction potential of DUT with azole antifungal drugs including KET, together with a newly developed HPLC-FL method for the simultaneous quantification of DUT and H-DUT. View Full-Text
Keywords: dutasteride; 6β-hydroxy dutasteride; HPLC; fluorescence; ketoconazole; CYP3A dutasteride; 6β-hydroxy dutasteride; HPLC; fluorescence; ketoconazole; CYP3A
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Seo, S.-W.; Park, J.W.; Han, D.-G.; Kim, J.-M.; Kim, S.; Park, T.; Kang, K.-H.; Yang, M.H.; Yoon, I.-S. In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole. Pharmaceutics 2019, 11, 673.

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