Effect of Multiple Dosing of Ketoconazole on Pharmacokinetics of Midazolam, a Cytochrome P-450 3A Substrate in Beagle Dogs

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

doi:10.1124/dmd.30.1.63

Cited by 56 publications

(60 citation statements)

References 26 publications

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“…Thus, caution should be taken when the KET is used as a CYP3A12 probe at higher concentrations. The inhibition kinetics of CYP3A-mediated DZ C3-hydroxylation in DLM displayed by KET (K i ϭ 0.13-0.33 M) are consistent with that of midazolam 1Ј-and 4-hydroxylations (K i ϭ 0.024 -0.11 M) (Kuroha et al, 2002).…”

Section: Discussionsupporting

confidence: 53%

“…The derivatives can inactivate P450 activities by mechanisms involving suicide inactivation, i.e., covalent modification of the prosthetic heme group (Mathews and Bend, 1986) and covalent modification of the apoprotein moiety (Woodcroft et al, 1997). On the other hand, ketoconazole (KET) has been well documented as an inhibitor of CYP3A in many species (www.druginteractioninfo.org; Baldwin et al, 1995;Sai et al, 2000;Kuroha et al, 2002).…”

mentioning

confidence: 99%

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Selective Inhibition of Dog Hepatic CYP2B11 and CYP3A12

Lü

Singh²,

Carr³

et al. 2005

J Pharmacol Exp Ther

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In the present study, N-(␣-methylbenzyl-)-1-aminobenzotriazole (MBA) and ketoconazole (KET) were identified as the inhibitors with selectivity toward dog CYP2B11 and CYP3A12, respectively. Their selectivity was evaluated using phenacetin, and DZ C3-hydroxylation (CYP3A12) activities in dog liver microsomes (DLM). MBA exhibited potent mechanism-based inhibition of DZ N1-demethylase activity catalyzed by both baculovirus-expressed CYP2B11 and DLM. In both cases, inhibition was characterized by a low K I (0.35 and 0.46 M, respectively) and high k inact (1.5 and 0.56 min Ϫ1 , respectively). Despite complete loss of DZ N1-demethylase activity in the presence of MBA, there was no significant loss of cytochrome P450 (P450) CO-binding spectrum. These data suggest that the inactivation involved covalent modification of P450 apoprotein, instead of the prosthetic heme moiety. A homology model of CYP2B11 was constructed, based on the crystal structure of rabbit CYP2C5, for docking the substrate (DZ) and the inhibitor (MBA), respectively. The model, within the limits of our approximations, helped explain the substrate specificity and inhibitor selectivity of CYP2B11. In contrast to MBA, KET was identified as a potent and selective reversible (competitive) inhibitor of CYP3A12 (K I ϭ 0.13-0.33 M). In fact, complete inhibition of CYP3A12-dependent DZ C3-hydroxylation was possible at a low KET concentration (1 M). Therefore, it is concluded that one can attempt to conduct P450 reaction phenotype studies with DLM using MBA and KET as selective inhibitors of CYP2B11 and CYP3A12, respectively. Dog is an important and commonly used species for the preclinical assessment of metabolism, pharmacokinetics, safety, and efficacy in drug discovery and preclinical development. Cytochromes P450 (P450s) in dog play a pivotal role in drug biotransformation and clearance. To date, nine dog cytochrome P450 genes have been isolated and sequenced:

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Section: Discussionsupporting

confidence: 53%

mentioning

confidence: 99%

Selective Inhibition of Dog Hepatic CYP2B11 and CYP3A12

Lü

Singh²,

Carr³

et al. 2005

J Pharmacol Exp Ther

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“…Midazolam was chosen as a marker for CYP3A activity. The comparative metabolism of midazolam by recombinant canine P450s has not been reported, but 1Ј-hydroxylation is a common marker activity of CYP3A isoforms evaluated in most mammalian liver microsomes including dogs (Kuroha et al, 2002;Regmi et al, 2007). Other substrates evaluated by Shou et al (2003) that were not considered here include diazepam, dextromethorphan, and testosterone.…”

Section: Discussionmentioning

confidence: 99%

“…Except for propofol, which was confirmed to be a CYP2B11 substrate (Hay Kraus et al, 2000), several of the compounds listed above may be administered for at least several days. For example, ketoconazole may be administered for months with high doses (5-40 mg/kg/day) and variable exposures (Plumb, 2005) and is capable of increasing the area under the curve of intravenous midazolam up to 4-fold (Kuroha et al, 2002). Ultimately, K i values would be determined for the other potent inhibitors identified here.…”

Section: Canine P450 Inhibition By Veterinary Medicinesmentioning

confidence: 99%

In Vitro Drug-Drug Interaction Screens for Canine Veterinary Medicines: Evaluation of Cytochrome P450 Reversible Inhibition

Aidasani

Zaya²,

Malpas³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Little information regarding the metabolic pathways of pharmaceutical agents administered to dogs, or the inhibition of those metabolic pathways, is available. Without this information, it is difficult to assess how combinations of drugs, whether new or old or approved or nonapproved, may increase the risk for metabolic drug-drug interactions in dogs. Because mammalian xenobiotic metabolism pathways often involve the hepatic cytochrome P450 (P450) monooxgenases, canine liver microsome P450 inhibition screens were tested to evaluate the potential metabolic drug interaction risk of commonly used veterinary medicines. A probe substrate cocktail was developed for four of the five major hepatic canine P450s and used to evaluate their inhibition by 45 canine therapeutic agents in a single-point IC 50 screen. Moderate inhibitors (>25%) were further characterized with an automated ninepoint IC 50 assay that identified ketoconazole, clomipramine, and loperamide as submicromolar CYP2D15 inhibitors. Additional inhibitors belonged to the antiemetic, antimitotic, and anxiolytic therapeutic classes. According to the marker activities, the relative frequency of P450 inhibition by isoform followed the sequence CYP2D15 > CYP2B11 > CYP2C21/41 > CYP3A12/26 > CYP1A1/2. The findings presented suggest there is some overlap in canine and human P450 inhibition specificity. However, occasional differences may give human drugs used off-label in dogs unexpected P450 inhibition profiles and, therefore, cause an unexpected drugdrug interaction risk.The number of reports describing the basic enzymology of drugmetabolizing enzymes in nonhuman species has increased the last decade. Notable examples include the characterization of several homologs of the major human xenobiotic-metabolizing cytochromes P450 that were cloned from canine hepatocytes (Roussel et al., 1998;Shou et al., 2003). Single nucleotide polymorphisms within canine P450s that alter activity have also been identified, as have P450 isoforms that appear to only be expressed in a fraction of the beagle population (Sakamoto et al., 1995;Blaisdell et al., 1998). More recently, three hepatic feline P450s cDNAs were characterized, two of which were expressed and characterized (Tanaka et al., 2005(Tanaka et al., , 2006. Whereas some of these reports bring a better understanding of when metabolism in preclinical species may or may not reflect the human situation (Martignoni et al., 2006;Turpeinen et al., 2007), there have been few reports on how specific P450s are inhibited by or metabolize pharmaceuticals used in the animal health field.For instance, in the development of new therapies for dogs, prediction of whether concomitant medications in the patient population may inhibit metabolic clearance pathways would be helpful in the assessment of the metabolic drug-drug interaction (DDI) potential. However, there is a lack of canine P450 inhibition data and understanding of basic canine enzymology that has caused in vitro canine drug interaction assessment to lag behind that of h...

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“…Cimetidine and some fluoroquinolones also increase theophyllin plasma levels by inhibiting CYP1A2 in dogs (Fink-Gremmels, 2008). Ketoconazole increases midazolam plasma levels by interacting with CYP3A4 (Kuroha et al, 2002). One of the most significant metabolic interaction is observed in case of macrolides or pleuromutilins and the ionophore antibiotics.…”

Section: Induction and Inhibition Of Enzymes Involved In Metabolismmentioning

confidence: 92%

Comparative Veterinary Pharmacokinetics

Jerzsele¹

2012

Readings in Advanced Pharmacokinetics - Theory, Methods and Applications

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Effect of Multiple Dosing of Ketoconazole on Pharmacokinetics of Midazolam, a Cytochrome P-450 3A Substrate in Beagle Dogs

Cited by 56 publications

References 26 publications

Selective Inhibition of Dog Hepatic CYP2B11 and CYP3A12

Selective Inhibition of Dog Hepatic CYP2B11 and CYP3A12

In Vitro Drug-Drug Interaction Screens for Canine Veterinary Medicines: Evaluation of Cytochrome P450 Reversible Inhibition

Comparative Veterinary Pharmacokinetics

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