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

Ji-Min Kim,Taeuk Park,Min Hye Yang,Dong-Gyun Han,In-Soo Yoon,Seong-Wook Seo,Kyung-Hwa Kang,Jin Woo Park,Sanghyun Kim

doi:10.3390/pharmaceutics11120673

Abstract

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.

Highlights

Dutasteride (DUT; Figure 1), marketed under the brand name Avodart (GlaxoSmithKline), is a selective, potent, competitive, and irreversible inhibitor of 5α-reductase (5AR) that catalyzes the intracellular conversion of testosterone to dihydrotestosterone [1]
The in vitro microsomal metabolism data presented in this study revealed that the metabolism of DUT was markedly reduced by KET, a potent inhibitor of CYP3A in rats and humans (Figures 6B and 7B) [26,27]
The new high-performance liquid chromatography with fluorescence detection (HPLC-FL) method offers several advantages including the simplicity of the sample preparation procedure, high extraction recovery, negligible matrix effect, and wide assay range that covers steady-state blood DUT concentrations observed in clinical settings

Summary

Introduction

Dutasteride (DUT; Figure 1), marketed under the brand name Avodart (GlaxoSmithKline), is a selective, potent, competitive, and irreversible inhibitor of 5α-reductase (5AR) that catalyzes the intracellular conversion of testosterone to dihydrotestosterone [1]. DUT, a dual inhibitor of type-1 and type-2 5AR, was approved by the US Food and Drug Administration (FDA) in 2001 for the treatment of symptomatic benign prostatic hyperplasia [6]. It was approved for androgenic alopecia in Korea and Japan [7]. Previous in vitro studies have shown that compared to finasteride, DUT more potently inhibited type-1 and type-2 5AR by 45- and 2.5-fold, respectively [8,9]

Methods

Discussion

Conclusion