Induction of intestinal cytochrome P450 (CYP3A) by rifampicin in beagle dogs

Kyokawa, Yoshimasa; Nishibe, Yasuhiro; Wakabayashi, Mitsuko; Harauchi, Toshio; Maruyama, Toshiyuki; Baba, Tsuneo; Ohno, Kouji

doi:10.1016/s0009-2797(01)00164-8

Cited by 25 publications

(21 citation statements)

References 23 publications

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“…The beagle dog was selected as an animal model because (1) the metabolic pathways of dogs are much closer to those of humans than those of rats and mice (the major metabolic pathway of GLS4 in rats and mice is ester hydrolysis, and the esterase activities in dogs and humans are considerably lower than those in mice and rats); (2) the plasma concentrations of ketoconazole and rifampicin after oral administration in dogs are also close to those in humans [16,17] ; and (3) the major isozyme of the CYP3A subfamily in canines is CYP3A12, which is www.chinaphar.com Zhou X et al Acta Pharmacologica Sinica npg C max , and CL/F. All these findings suggested that GLS4 was a sensitive substrate of CYP3A, and first-pass metabolism played an important role in GLS4 elimination.…”

Section: Discussionmentioning

confidence: 99%

“…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. Therefore, the effects of ketoconazole and rifampicin on dog CYP3A activities are similar to those on human CYP3A activities, and beagle dogs are appropriate animal models for predicting drug interactions between CYP3A modulators and GLS4.…”

Section: Pharmacokinetics Of Gls4 Affected By Rifampicinmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

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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“…The reported studies in dogs mainly focus on the expression and catalytic activity of metabolic enzymes in the liver (Kyokawa et al, 2001;Mills et al, 2010). Less is known about the intestinal expression distribution of cytochromes P450 (P450s), UDP-glucuronosyltransferases (UGTs) (Bock et al, 2002;Mealey et al, 2008), and transporters (Conrad et al, 2001) or about P450 substrate specificity (Fraser et al, 1997;Turpeinen et al, 2007;Locuson et al, 2009) and intersubject variability in expression.…”

Section: Introductionmentioning

confidence: 99%

Expression Profiles of Metabolic Enzymes and Drug Transporters in the Liver and along the Intestine of Beagle Dogs

Haller¹,

Schuler²,

Lazic³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Beagle dogs are widely used in preclinical pharmacokinetic, safety, and formulation studies. However, little is known about intestinal and hepatic distribution of major enzymes and transporters involved in oral absorption and presystemic drug metabolism. We characterized mRNA levels of CYP3A12, CYP3A26, CYP2D15, UGT1A6, ABCB1 (MDR1), ABCC1 (MRP1), ABCG2 (BCRP), SLC15A1 (PEPT1), and SLC22A1 (OCT1) in dog liver and along the intestine by real-time quantitative reverse transcription-polymerase chain reaction. Tissue protein levels of CYP2D15, MDR1, and PEPT1 were obtained by Western blot. Gene distribution and expression variability was statistically described by a generalized additive mixed model smoothing function and correspondence analysis. Results were compared with the expression pattern known for the human orthologs. Hepatic mRNA levels for metabolic enzymes were generally higher than those for membrane transporters, whereas in the intestine the opposite was observed. Hepatic mRNA levels followed the order CYP2D15 > UGT1A6 Ϸ CYP3A26 > ABCB1 Ϸ SLC15A1 Ϸ SLC22A1 > ABCG2 > ABCC1 Ϸ CYP3A12. Along the gut, the genes were differentially distributed with greatest expression in duodenum/upper jejunum (ABCG2), middle jejunum (ABCB1 and SLC15A1), or in cecum/colon (ABCC1 and CYP2D15). CYP3A12, CYP3A26, SLC22A1, and UGT1A6 had a rather uniform expression. Intestinal mRNA profiles of CYP2D15, ABCB1, and SLC15A1 correlated with the respective protein levels. Canine CYP3A12/26, CYP2D15, and ABCB1 colonic distributions differed from those of human orthologs, whereas UGT1A6, ABCC1, ABCG2, SLC15A1, and SLC22A1 were comparable to those of humans in both small and large intestine. We aim to apply these data to better interpret pharmacokinetic studies in dogs with respect to their human relevance.

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“…Intestinal extraction is known to play a large role in human midazolam interactions. Dog CYP3A-like activities and mRNA levels have been reported (Kyokawa et al, 2001;Mealey et al, 2008), but the authors are not aware of other activities/ isoforms having been quantitatively assessed in canine intestinal tissue. Therefore, it has been assumed here that there is an intestinal DDI component resulting from P450 inhibition with the realization that the exact contribution of CYP3A, CYP2B, or CYP2C enzymes remains unknown.…”

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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Induction of intestinal cytochrome P450 (CYP3A) by rifampicin in beagle dogs

Cited by 25 publications

References 23 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

Expression Profiles of Metabolic Enzymes and Drug Transporters in the Liver and along the Intestine of Beagle Dogs

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

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