In vitro characterization of the inhibitory effects of ketoconazole on metabolic activities of cytochrome P-450 in canine hepatic microsomes

Kuroha, Masanori; Kuze, Yoji; Shimoda, Minoru; Kokue, Eiichi

doi:10.2460/ajvr.2002.63.900

Cited by 35 publications

(44 citation statements)

References 18 publications

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“…In particular, the human ketoconazole-midazolam interaction is very established so it is usually the first substrate/inhibitor pair to be tested in vitro with liver microsomes from lesser characterized species. In addition, CYP3A probes such as midazolam are cleared quickly in dog liver microsomes, and ketoconazole was demonstrated to have submicromolar inhibition constants against midazolam in liver microsomes (Kuroha et al, 2002b;Aidasani et al, 2008). Similar in vivo interactions were reproduced here with ketoconazole and midazolam (Table 5), and ketoconazole was verified to be a very potent inhibitor of recombinant CYP3A12.…”

Section: Discussionsupporting

confidence: 60%

“…Inhibition constants (IC 50 or K i ) were determined for several rP450-inhibitor combinations after determining the isoforms with the highest intrinsic clearances for each victim drug (see below) ( Table 4). All but one inhibition constant was Ͻ10 M, and the majority of unbound inhibition constants were Ͻ1 M. Although suspected earlier based on liver microsome findings (Kuroha et al, 2002b), ketoconazole was verified to be a potent inhibitor of canine recombinant CYP3A12 (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

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Current Cytochrome P450 Phenotyping Methods Applied to Metabolic Drug-Drug Interaction Prediction in Dogs

Mills

Zaya²,

Walters³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Recombinant cytochrome P450 (P450) phenotyping, different approaches for estimating fraction metabolized (f m ), and multiple measures of in vivo inhibitor exposure were tested for their ability to predict drug interaction magnitude in dogs. In previous reports, midazolam-ketoconazole interaction studies in dogs have been attributed to inhibition of CYP3A pathways. However, in vitro phenotyping studies demonstrated higher apparent intrinsic clearances (CL int,app ) of midazolam with canine CYP2B11 and CYP2C21. Application of activity correction factors and isoform hepatic abundance to liver microsome CL int,app values further implicated CYP2B11 (f m > 0.89) as the dog enzyme responsible for midazolam-and temazepam-ketoconazole interactions in vivo. Mean area under the curve (AUC) in the presence of the inhibitor/AUC ratios from intravenous and oral midazolam interaction studies were predicted well with unbound K i and estimates of unbound hepatic inlet inhibitor concentrations and intestinal metabolism using the AUC-competitive inhibitor relationship. No interactions were observed in vivo with bufuralol, although significant interactions with bufuralol were predicted with fluoxetine via CYP2D and CYP2C pathways (>2.45-fold) but not with clomipramine (<2-fold). The minor caffeine-fluvoxamine interaction (1.78-fold) was slightly higher than predicted values based on determination of a moderate f m value for CYP1A1, although CYP1A2 may also be involved in caffeine metabolism. The findings suggest promise for in vitro approaches to drug interaction assessment in dogs, but they also highlight the need to identify improved substrate and inhibitor probes for canine P450s.Metabolism-mediated drug interactions are an important consideration during preclinical drug lead optimization. Inhibitors of drugmetabolizing enzymes such as cytochromes P450 (P450) may be capable of decreasing the clearance of coadministered drugs when their clearance is metabolic. Therefore, it is important to evaluate new chemical entities as substrates and inhibitors of P450. To speed up this evaluation process, in vitro-in vivo extrapolation methods aimed at predicting metabolic drug interactions have continued to evolve. For instance, the choice of inhibition values (e.g., K i versus unbound K i ) (Brown et al., 2006), inhibitor absorption rates (Kanamitsu et al., 2000;Brown et al., 2005), P450 induction , and the choice of in vivo concentrations of P450 inhibitors (Brown et al., 2005;Obach et al., 2005) have all been studied with respect to in vitro-based drug-drug interaction (DDI) predictions. Irreversible enzyme inhibition mechanisms, although recognized for some time, have increasingly been added to in vitro-based drug interaction extrapolation methods with assumptions about the turnover rates of P450 isoforms (Mayhew et al., 2000;Venkatakrishnan and Obach, 2007). Several of these in vitro findings or approaches have even been integrated into several commercial software packages as biology continues to advance toward more physiolog...

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Section: Discussionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Current Cytochrome P450 Phenotyping Methods Applied to Metabolic Drug-Drug Interaction Prediction in Dogs

Mills

Zaya²,

Walters³

et al. 2009

Drug Metab Dispos

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“…Ketoconazole can competitively inhibit CYP3A12 activities [19] and at a therapeutic dose can largely decrease the total body clearance of the CYP3A substrates such as midazolam and nifedipine. Therefore, the beagle dog can be used as an animal model to predict drugdrug interactions between ketoconazole and CYP3A substrates in clinical practice [20] .…”

Section: Pharmacokinetics Of Gls4 Affected By Rifampicinmentioning

confidence: 99%

Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs

Zhou

Gao

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the metabolism of GLS4, a heteroaryldihydropyrimidine compound with anti-hepatitis B virus activity, in dog and human liver microsomes in vitro and evaluate the effects of ketoconazole (a potent CYP3A inhibitor) or rifampicin (a potent CYP3A inducer) on GLS4 pharmacokinetics in dogs. Methods: Dog and human liver microsomes and CYP3A4 were incubated with [14 C]GLS4 for 15 min and then analyzed using a HPLCdynamic online radio flow detection method. Two groups of beagle dogs were used for in vivo studies. Group A were orally administered a single dose of GLS4 (15 mg/kg) with or without ketoconazole pretreatment (100 mg/d for 8 consecutive days). Group B were orally administered a single dose of GLS4 (15 mg/kg) with or without rifampicin pretreatment (100 mg/d for 8 consecutive days). Plasma was sampled after GLS4 dosing. GLS4 concentrations were determined by HPLC-tandem mass spectrometry. Results: The metabolic profile of [14 C]GLS4 in human and dog liver microsomes and CYP3A4 was similar. The major metabolites were morpholine N-dealkylated GLS4 and morpholine N,N-di-dealkylated GLS4. Pretreatment with ketoconazole or rifampicin significantly affected the plasma concentrations of GLS4 in dogs: ketoconazole increased the area under the concentration-time curve from 0 to infinity and peak concentration of GLS4 by 4.4 and 3.3 folds, respectively, whereas rifampicin decreased these parameters by 88.5% and 83.2%, respectively. Conclusion: GLS4 is a sensitive substrate of CYP3A. CYP3A inhibitors or inducers cause considerable change of GLS4 plasma concentrations in dogs, which should be considered in clinical practice.

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“…Ciclosporin is primarily metabolized in the liver by cytochrome P450 enzymes 2B11 and 3A12 ⁄ 26. 8,9 Consequently, research thus far has focused on pharmacotherapeutic manipulation of this enzyme system by co-administration of drugs known to be P450-enzyme inhibitors. Recent studies indicate that neither metoclopramide nor cimetidine, both P450 inhibitors, have any effect on the pharmacokinetic profile of concurrently administered CSA.…”

Section: Introductionmentioning

confidence: 99%

“…11,12 Ketoconazole (KTZ) is a potent inhibitor of numerous cytochrome P450 enzymes, including CYP 2B11 and 3A12 ⁄ 26. 8,9 Numerous in vitro and in vivo studies have demonstrated that co-administration of KTZ with CSA results in increased whole blood CSA concentrations in dogs. [13][14][15][16][17][18] The inhibitory effect of KTZ on CSA clearance from blood was determined to be dose dependent, with the critical KTZ dosage range identified as 2.5-10 mg ⁄ kg daily.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Ketoconazole on Whole Blood and Skin Ciclosporin Concentrations in Dogs

Gray¹,

Hillier²,

Cole³

et al. 2013

Advances in Veterinary Dermatology

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In vitro characterization of the inhibitory effects of ketoconazole on metabolic activities of cytochrome P-450 in canine hepatic microsomes

Cited by 35 publications

References 18 publications

Current Cytochrome P450 Phenotyping Methods Applied to Metabolic Drug-Drug Interaction Prediction in Dogs

Current Cytochrome P450 Phenotyping Methods Applied to Metabolic Drug-Drug Interaction Prediction in Dogs

Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs

The Effect of Ketoconazole on Whole Blood and Skin Ciclosporin Concentrations in Dogs

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