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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 5?-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, 6?-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.

SUBMITTER: Seo SW

PROVIDER: S-EPMC6956158 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Seo Seong-Wook SW Park Jin Woo JW Han Dong-Gyun DG Kim Ji-Min JM Kim Sanghyun S Park Taeuk T Kang Kyung-Hwa KH Yang Min Hye MH Yoon In-Soo IS

Pharmaceutics 20191211 12

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 ...[more]

PMID: 31835695

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Project description:AimsCanagliflozin is a recently approved drug for use in the treatment of type 2 diabetes. The potential for canagliflozin to cause clinical drug-drug interactions (DDIs) was assessed.MethodsDDI potential of canagliflozin was investigated using in vitro test systems containing drug metabolizing enzymes or transporters. Basic predictive approaches were applied to determine potential interactions in vivo. A physiologically-based pharmacokinetic (PBPK) model was developed and clinical DDI simulations were performed to determine the likelihood of cytochrome P450 (CYP) inhibition by canagliflozin.ResultsCanagliflozin was primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase 1A9 and 2B4 enzymes. Canagliflozin was a substrate of efflux transporters (P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated protein-2) but was not a substrate of uptake transporters (organic anion transporter polypeptide isoforms OATP1B1, OATP1B3, organic anion transporters OAT1 and OAT3, and organic cationic transporters OCT1, and OCT2). In inhibition assays, canagliflozin was shown to be a weak in vitro inhibitor (IC50 ) of CYP3A4 (27 μmol l -1 , standard error [SE] 4.9), CYP2C9 (80 μmol l -1 , SE 8.1), CYP2B6 (16 μmol l-1 , SE 2.1), CYP2C8 (75 μmol l -1 , SE 6.4), P-glycoprotein (19.3 μmol l -1 , SE 7.2), and multidrug resistance-associated protein-2 (21.5 μmol l -1 , SE 3.1). Basic models recommended in DDI guidelines (US Food & Drug Administration and European Medicines Agency) predicted moderate to low likelihood of interaction for these CYPs and efflux transporters. PBPK DDI simulations of canagliflozin with CYP probe substrates (simvastatin, S-warfarin, bupropion, repaglinide) did not show relevant interaction in humans since mean areas under the concentration-time curve and maximum plasma concentration ratios for probe substrates with and without canagliflozin and its 95% CIs were within 0.80-1.25.ConclusionsIn vitro DDI followed by a predictive or PBPK approach was applied to determine DDI potential of canagliflozin. Overall, canagliflozin is neither a perpetrator nor a victim of clinically important interactions.

Project description:BACKGROUND AND OBJECTIVES:Darolutamide is a novel androgen receptor (AR) antagonist approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). Accordingly, the drug-drug interaction (DDI) potential of darolutamide was investigated in both nonclinical and clinical studies. METHODS:In vitro studies were performed to determine the potential for darolutamide to be a substrate, inducer or inhibitor for cytochrome P450 (CYP) isoforms, other metabolizing enzymes and drug transporters. A phase I drug-interaction study in healthy volunteers evaluated the impact of co-administering rifampicin [CYP3A4 and P-glycoprotein (P-gp) inducer] and itraconazole [CYP3A4, P-gp and breast cancer resistance protein (BCRP) inhibitor] on the pharmacokinetics of darolutamide. Two further phase I studies assessed the impact of co-administering oral darolutamide on the pharmacokinetics of midazolam (sensitive CYP3A4 substrate) and dabigatran etexilate (P-gp substrate) and the impact on the pharmacokinetics of co-administered rosuvastatin [a substrate for BCRP, organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and organic anion transporter (OAT)3]. RESULTS:In vitro, darolutamide was predominantly metabolized via oxidative biotransformation catalyzed by CYP3A4 and was identified as a substrate for P-gp and BCRP. The enzymatic activity of nine CYP isoforms was not inhibited or slightly inhibited in vitro with darolutamide, and a rank order and mechanistic static assessment indicated that risk of clinically relevant DDIs via CYP inhibition is very low. In vitro, darolutamide exhibited no relevant induction of CYP1A2 or CYP2B6 activity. Inhibition of BCRP-, P-gp-, OAT3-, MATE1-, MATE2-K-, OATP1B1- and OATP1B3-mediated transport was observed in vitro. Phase I data showed that darolutamide exposure increased 1.75-fold with co-administered itraconazole and decreased by 72% with rifampicin. Co-administration of darolutamide with CYP3A4/P-gp substrates showed no effect or only minor effects. Rosuvastatin exposure increased 5.2-fold with darolutamide because of BCRP and probably also OATPB1/OATPB3 inhibition. CONCLUSIONS:Darolutamide has a low potential for clinically relevant DDIs with drugs that are substrates for CYP or P-gp; increased exposure of BCRP and probably OATP substrates was the main interaction of note.

Project description:Background and objectivesOcedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. This study evaluated the involvement of cytochrome P450 (CYP) isozymes and drug transporters in the biotransformation of ocedurenone, and whether ocedurenone inhibited or induced CYP enzymes and transporters. Clinical pharmacokinetic drug-drug interaction (DDI) of ocedurenone with CYP3A inhibitor and inducer were investigated in healthy volunteers.MethodsIn vitro tests were conducted to determine which CYP enzymes were involved in ocedurenone's metabolism and whether ocedurenone inhibited or induced these CYP enzymes; ocedurenone substrate characteristics for efflux and uptake transporters and its inhibitory potential on major drug transporters were also assessed. A clinical DDI study was conducted in healthy volunteers to evaluate the effects of a strong CYP3A inhibitor (itraconazole) and inducer (rifampin) on ocedurenone's pharmacokinetics.ResultsThe in vitro study showed that ocedurenone was primarily metabolized by CYP3A4 and that it did not inhibit CYP enzymes. Ocedurenone appeared to be a substrate of BCRP and P-gp efflux transporters and inhibited BCRP, BSEP, MDR1, MATE1 and 2-K, OATP1B1/3, and OCT1. The clinical DDI study showed that itraconazole reduced ocedurenone's oral clearance by 51% and increased area under the plasma concentration-time curve extrapolated to infinity (AUC0-inf) by 104%, while rifampin increased its oral clearance by 6.4-fold and decreased plasma AUC0-inf by 84%.ConclusionOcedurenone was shown to be a CYP3A substrate, with no inhibition potential on major drug metabolizing CYP enzymes and transporters at clinical efficacious doses. Ocedurenone did not induce CYP1A2 and 3A4 activity in cultured human primary hepatocytes. Clinical DDI study indicated ocedurenone was well tolerated when administered as a single 0.5-mg dose both alone and with itraconazole or rifampin, and while itraconazole had a weak effect on ocedurenone's pharmacokinetics, rifampin had a significant effect reducing systemic exposures.

Project description:Objective: Theacrine, a methylurate class purine alkaloid, triggers diverse pharmacologic responses, including psychostimulatory activity by modulation of adenosinergic and dopaminergic pathways. In a double-blind, placebo-controlled study, theacrine increased energy, concentration, and mood, while reducing fatigue. Because caffeine, a methylxanthine purine alkaloid, is frequently coadministered with theacrine, we sought to determine if a pharmacokinetic and/or pharmacodynamic interaction existed between theacrine and caffeine. Methods: Eight healthy adults received theacrine, as TeaCrine® (25 or 125?mg), caffeine (150?mg), or a combination of theacrine (125?mg) and caffeine (150?mg) in a randomized, double-blind crossover study. Blood samples were collected over a 24-hour period and analyzed by Liquid chromatrography-mass spectrometry/mass spectrometry (LC-MS/MS) for theacrine, caffeine, and paraxanthine. Pharmacodynamic response markers, heart rate and blood pressure, were recorded. Results: Theacrine pharmacokinetics was similar following administration of theacrine alone. Caffeine coadministration increased maximum plasma concentration and area under the curve of theacrine without altering theacrine half-life. Theacrine had no impact on caffeine or paraxanthine pharmacokinetics. There was no difference between treatment groups with regard to heart rate or systolic/diastolic blood pressure. Conclusions: Coadministration of theacrine and caffeine results in a clinically significant pharmacokinetic interaction, viz., increased theacrine exposure. Enhanced oral bioavailability is the most likely mechanism by which caffeine alters theacrine exposure. However, further studies examining the contribution of presystemic elimination mechanisms, for example, efflux transport and/or gut metabolism, to theacrine bioavailability are needed to confirm the exact mechanism(s). Hemodynamic parameters were unaltered despite the pharmacokinetic interaction, suggesting that coadministration of caffeine and theacrine is safe at the doses administered.

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

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

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