Multiple oral dosing of ketoconazole influences pharmacokinetics of quinidine after intravenous and oral administration in beagle dogs

Kuroha, Masanori; Shirai, Yuko; Shimoda, Minoru

doi:10.1111/j.1365-2885.2004.00610.x

Cited by 15 publications

(16 citation statements)

References 13 publications

(24 reference statements)

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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] . Kyokawa et al [17] reported that the beagle dog can be a suitable animal model for predicting the induction of both hepatic and intestinal CYP3A in humans.…”

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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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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“…This extent was similar to those in hepatic microsomes from dogs treated with DEX in our previous study. Since QN is mainly metabolized by CYP3A [11] and is categorized as a drug with low hepatic extraction [2], our present study suggests that DEX treatment at clinical doses significantly decreases CYP3A activity, even in intact dogs, and thereby significantly alters the pharmacokinetics of the CYP3A substrate.…”

Section: Discussionmentioning

confidence: 66%

“…Because of this, we examined the effect of clinical doses of DEX on the pharmacokinetics of a CYP3A substrate, quinidine (QN), in dogs. We selected this drug because it is mainly metabolized by CYP3A [11] and is subjected to low hepatic extraction in dogs [2]. …”

mentioning

confidence: 99%

Clinical Oral Doses of Dexamethasone Decreases Intrinsic Clearance of Quinidine, A Cytochrome P450 3A Substrate in Dogs

Zhang

Kohno

Kuroha

et al. 2006

The Journal of Veterinary Medical Science

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ABSTRACT. We investigated the effect of dexamethasone (DEX) at clinical doses on the pharmacokinetics of quinidine (QN) in dogs. Dogs (5 healthy 1-year-old male beagles) were orally administered DEX once daily for 5 days at 2.5 or 7.5 mg/day. QN (2 mg/kg) was intravenously injected 3 weeks before and one day after the DEX treatment. The plasma concentration of QN was determined by high-performance liquid chromatography with fluorometric detection. Plasma concentrations of albumin and α 1 -acid glycoprotein (AGP) were determined by a bromocresol green method and a single immunodiffusion method, respectively. In order to calculate unbound concentrations of QN in plasma, the binding kinetics of QN in plasma was examined by an ultrafiltration method using pooled plasma from the 5 dogs when they were drug-free. Total body clearance of QN was decreased dose-dependently By the DEX treatment, although the decrease was not statistically significant. Elimination half-lives significantly increased (more than twice at 7.5 mg), and intrinsic clearance significantly decreased (about 50%). The volume of distribution increased significantly (about two-fold). Plasma levels of AGP significantly decreased, and the unbound fraction of QN in plasma significantly increased. Our results demonstrate that clinical doses of DEX significantly affect the pharmacokinetics of QN, a CYP3A substrate in dogs, by decreasing CYP3A activity and plasma AGP levels. There is a possibility that adverse drug-drug interaction occurs during DEX therapy through its effects on CYP3A activity and plasma AGP levels. KEY WORDS: canine, clearance, CYP3A, dexamethasone, quinidine.J. Vet. Med. Sci. 68(9): 903-907, 2006 Drug metabolism is one of the determinant factors of drug disposition. Alterations in drug metabolism are, therefore, a matter of primary concern for many researchers not only in human medicine, but also veterinary medicine. Although altered drug metabolism may result from several factors, enzyme inhibition has been extensively studied and recognized as the most important factor requiring a great deal of attention in the clinical state because it may lead to fetal toxicity of co-administered drugs in some cases [6].DEX is a well-established inducer of the cytochrome P450 (CYP) 3A subfamily. There are many reports that describe induction of CYP3A through in vitro [14,10] and in vivo studies [7,17,19]. However, very high doses (more than 10 times of the clinical dose) were used in most of the in vivo studies. In canine clinics, the recommended doses of DEX are 0.05-0.3 mg/kg/day for anti-inflammatory therapy and 0.5-1 mg/kg/day for acute adrenocortical collapse and immunosuppressive therapy [4]. In our previous study [21], therefore, we examined the inducing effect of DEX on CYP3A using clinical doses in dogs and rats. Although Jayyosi et al. reported that there is no significant induction of CYP3A in dogs treated with DEX (50 mg/kg for 5 days), we observed a decrease of about 70% in the maximum reaction velocities of midazolam 4-hydroxylation in...

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“…Interactions in dogs involving ketoconazole have previously been attributed to CYP3A pathways (Kuroha et al, 2002a(Kuroha et al, , 2004. 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.…”

Section: Discussionmentioning

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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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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Multiple oral dosing of ketoconazole influences pharmacokinetics of quinidine after intravenous and oral administration in beagle dogs

Cited by 15 publications

References 13 publications

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

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

Clinical Oral Doses of Dexamethasone Decreases Intrinsic Clearance of Quinidine, A Cytochrome P450 3A Substrate in Dogs

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

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