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

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.

Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

“…Assuming that RPG is metabolized exclusively by the liver, the hepatic clearance (CL H ) of RPG becomes equivalent to its blood clearance (calculated as CL/R B = 9.11 mL/min/kg). Thus, the hepatic extraction ratio (E H ) of RPG can be estimated to be 0.114–0.182, by dividing the CL H by the rat hepatic blood flow (Q H , 50–80 mL/min/kg) [ 47 ]. The CL H of a drug with a low E H primarily depends on its unbound fraction in the blood (f B ) and CL int , based on the well-stirred hepatic clearance model.…”

Investigation of the factors responsible for the low oral bioavailability of alizarin using a sensitive LC‐MS/MS method: In vitro, in situ, and in vivo evaluations

“…The blood samples were centrifuged at 2000 g for 5 min at 4°C to obtain 120 μL of plasma. Urine was collected throughout the blood sampling period of 24 h, and the entire gut luminal content (including feces) was removed and extracted with methanol, as described previously (Seo et al, 2019). The urine and gut samples were analyzed using the LC‐MS/MS method to determine the total amount of alizarin excreted in urine during 24 h (Ae U ) and the total amount of alizarin recovered from gut luminal contents during the 24 h (Ae G ).…”

Investigation of the Factors Responsible for the Poor Oral Bioavailability of Acacetin in Rats: Physicochemical and Biopharmaceutical Aspects

“…The fractions of unbound acacetin in plasma (fu P ), microsomes (fu MIC ), SGF (fu SGF ), and SIF(fu SIF ) were measured using a rapid equilibrium dialysis device (Thermo Fisher Scientific, Inc., Waltham, MA, USA) as previously described with slight modifications [ 25 ]. Briefly, 0.2 mL of the matrix spiked with acacetin (10 μM) was placed into the “sample” chamber, and 0.4 mL of PBS was placed into the adjacent “buffer” chamber.…”

“…The fractions of unbound acacetin were calculated as the concentration ratio between the two chambers. The blood-to-plasma concentration ratio (R B ) of acacetin was determined as described previously [ 25 ]. Briefly, 1-mL blood spiked with acacetin (1 μM) was incubated at 37 °C for 30 min.…”