In Vivo Evaluation of Drug-Drug Interaction via Mechanism-Based Inhibition by Macrolide Antibiotics in Cynomolgus Monkeys

Ogasawara, Akihito; Negishi, Isao; Kozakai, Kazumasa; Kume, Toshiyuki

doi:10.1124/dmd.109.028969

Cited by 10 publications

(9 citation statements)

References 35 publications

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“…Although the single dosing regimen used in this study may not be sufficient to produce the maximal level of enzyme inactivation by compound A, the magnitude increase in midazolam AUC i,pv by compound A was nevertheless close to the anticipated range based on the values of k inact and K I obtained in this study and using a quantitative prediction method proposed for mechanismbased inactivators by Ernest et al (89). Encouragingly, similar observations were also made by other researchers in cynomolgus monkeys, whether by reversible or mechanismbased inhibition (53,90).…”

Section: Cyp3a-mediated Ddis In Monkeyssupporting

confidence: 88%

“…However, potent reversible human CYP3A inhibitors, such as ketoconazole, appear to have reasonable cross-activity in many species, as shown by the comparable K i or IC 50 values determined in multiple species (51,52). Some mechanism-based CYP3A4 inhibitors also are effective for CYP3A of cynomolgus monkeys (53) and rats (54). Thus, DDIs caused by CYP3A inhibition may be reasonably reflected by multiple animal models.…”

Section: Metabolism Modelsmentioning

confidence: 99%

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Use of In Vivo Animal Models to Assess Pharmacokinetic Drug-Drug Interactions

Tang

Prueksaritanont

2010

Pharm Res

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Animal models are used commonly in various stages of drug discovery and development to aid in the prospective assessment of drug-drug interaction (DDI) potential and the understanding of the underlying mechanism for DDI of a drug candidate. In vivo assessments in an appropriate animal model can be very valuable, when used in combination with in vitro systems, to help verify in vivo relevance of the in vitro animal-based results, and thus substantiate the extrapolation of in vitro human data to clinical outcomes. From a pharmacokinetic standpoint, a key consideration for rational selection of an animal model is based on broad similarities to humans in important physiological and biochemical parameters governing drug absorption, distribution, metabolism or excretion (ADME) processes in question for both the perpetrator and victim drugs. Equally critical are specific in vitro and/or in vivo experiments to demonstrate those similarities, usually both qualitative and quantitative, in the ADME properties/processes under investigation. In this review, theoretical basis and specific examples are presented to illustrate the utility of the animal models in assessing the potential and understanding the mechanisms of DDIs.

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Section: Cyp3a-mediated Ddis In Monkeyssupporting

confidence: 88%

Section: Metabolism Modelsmentioning

confidence: 99%

Use of In Vivo Animal Models to Assess Pharmacokinetic Drug-Drug Interactions

Tang

Prueksaritanont

2010

Pharm Res

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“…Involvement of CYP2C76 in species differences, however, does not preclude the use of cynomolgus monkeys in preclinical studies, as cynomolgus monkeys are useful for in vivo ADMET (absorption, distribution, metabolism, excretion, and toxicity) and DDI (drug-drug interaction) studies (e.g. refs [57][58][59][60][61]). …”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Macaque CYP2C76 Encodes Cytochrome P450 Enzyme Not Orthologous to Any Human Isozymes

Uno

Fujino²,

Iwasaki³

et al. 2010

CDM

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Cynomolgus monkey is used in the study of drug metabolism and toxicity due to its evolutionary closeness to human as compared with other non-human primate species. However, it has become certain that drug metabolism in monkeys is different than in humans. Such species differences have not been fully investigated at a molecular level largely due to the scarcity of information on drug-metabolizing enzyme genes. In cynomolgus monkey, we have identified cDNAs for 21 kinds of cytochromes P450 (CYPs), among which CYP2C76 does not correspond to any human CYP isozymes and is partly responsible for the difference in pitavastatin metabolism between cynomolgus monkey and human. In cynomolgus monkey CYP2C76, we identified numerous genetic variants including a null genotype. Heterozygotes for this null genotype are expected to be poor metabolizers in CYP2C76-mediated drug metabolism. To provide new clues to CYP2C76 function, here, we have taken advantage of sequence information that has been recently deposited to public databases to assess the presence of CYP2C76 orthologs in primate species. In this assessment, we found the CYP2C76 cDNA sequence in rhesus monkey, and a gene sequence highly homologous to cynomolgus monkey CYP2C76 in the marmoset and orangutan genomes, raising the possibility that CYP2C76 could also play a role in these primate species. This review paper gives an overview of CYP2C76 from isolation to molecular characterization, and its implication in drug metabolism.

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“…Recent studies have identified a number of P450 cDNAs from cynomolgus monkeys, including those of CYP3A8 and CYP3A5, which show high sequence identities (94 -95%) with the orthologous human CYP3A4 and CYP3A5, respectively (Uno et al, 2007(Uno et al, , 2010Iwasaki and Uno, 2009). Furthermore, when an oral dose of CYP3A substrates, such as midazolam (MDZ) and simvastatin, was coadministered with typical CYP3A inhibitors, these monkeys showed markedly higher plasma concentrations than those who received a dose of substrate alone (Kanazu et al, 2004;Ogasawara et al, 2007Ogasawara et al, , 2009a. These findings suggest that monkeys can be used to investigate the underlying mechanism of and to predict the likelihood of clinical DDIs when CYP3A inhibition is involved.…”

Section: Introductionmentioning

confidence: 99%

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Ohtsuka¹,

Yoshikawa²,

Kozakai³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Induction of the cytochrome P450 (P450) enzyme is a major concern in the drug discovery processes. To predict the clinical significance of enzyme induction, it is helpful to investigate pharmacokinetic alterations of a coadministered drug in a suitable animal model. In this study, we focus on the induction of CYP3A, which is involved in the metabolism of approximately 50% of marketed drugs and is inducible in both the liver and intestine. As a marker substrate for CYP3A activity, alprazolam (APZ) was selected and characterized using recombinant CYP3A enzymes expressed in Escherichia coli. Both human CYP3A4 and its cynomolgus P450 ortholog predominantly catalyzed APZ 4-hydroxylation with sigmoidal kinetics. When administered intravenously and orally to cynomolgus monkeys, APZ had moderate clearance; its first-pass extraction ratio after oral dosing was estimated to be 0.09 in the liver and 0.45 in the intestine. Pretreatment with multiple doses of rifampicin (20 mg/kg p.o. for 5 days), a known CYP3A inducer, significantly decreased plasma concentrations of APZ after intravenous and oral administrations (0.5 mg/kg), and first-pass extraction ratios were increased to 0.39 in the liver and 0.63 in the intestine. The results were comparable to those obtained in clinical drug-drug interaction (DDI) reports related to CYP3A induction, although the rate of recovery of CYP3A activity seemed to be slower than rates estimated in clinical studies. In conclusion, pharmacokinetic studies using APZ as a probe in monkeys may provide useful information regarding the prediction of clinical DDIs due to CYP3A induction.

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In Vivo Evaluation of Drug-Drug Interaction via Mechanism-Based Inhibition by Macrolide Antibiotics in Cynomolgus Monkeys

Cited by 10 publications

References 35 publications

Use of In Vivo Animal Models to Assess Pharmacokinetic Drug-Drug Interactions

Use of In Vivo Animal Models to Assess Pharmacokinetic Drug-Drug Interactions

Macaque CYP2C76 Encodes Cytochrome P450 Enzyme Not Orthologous to Any Human Isozymes

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

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