Characterization of cynomolgus monkey cytochrome P450 (CYP) cDNAs: Is CYP2C76 the only monkey-specific CYP gene responsible for species differences in drug metabolism?

Uno, Yasuhiro; Hosaka, Shinya; Matsuno, Kiyomi; Nakamura, Chika; Kito, Go; Kamataki, Tetsuya; Nagata, Ryoichi

doi:10.1016/j.abb.2007.07.003

Cited by 66 publications

(70 citation statements)

References 25 publications

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“…3). The excellent correlation was consistent with previous reports that showed similarities in amino acid sequences of drug-metabolizing enzymes between monkeys and humans, CYP3A8 and CYP3A5 in monkeys having especially high homology (Ͼ90%) to CYP3A4 and CYP3A5, respectively, in humans (Komori et al, 1992;Shimada et al, 1997;Uno et al, 2007). The fitting line of the relationship was 2.3-fold higher in monkeys than in humans (Table 1; Fig.…”

Section: Discussionsupporting

confidence: 80%

“…Monkeys may be appropriate animal models, because of their greater similarities with humans in amino acid sequences of drug-metabolizing enzymes (Komori et al, 1992;Shimada et al, 1997;Uno et al, 2007). Indeed, it has been reported that human pharmacokinetics after intravenous administration of an investigational drug can be predicted more accurately from results obtained in monkeys than from those in rats and dogs (Ward and Smith, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Prediction of the Intestinal First-Pass Metabolism of CYP3A Substrates in Humans Using Cynomolgus Monkeys

Nishimuta¹,

Sato²,

Mizuki³

et al. 2010

Drug Metab Dispos

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ABSTRACT:To select high bioavailability compounds, it is necessary to predict the first-pass metabolism in the intestine. However, in vitro-in vivo predictions of the intestinal metabolism have proven both challenging and less definitive. The purpose of this study was to investigate prediction of intestinal first-pass metabolism in humans using cynomolgus monkeys. First, we investigated intrinsic metabolic activities in intestinal microsomes of monkeys (MIM) and humans (HIM) (CL int, MIM and CL int, HIM , respectively) of 18 CYP3A substrates. The CL int, MIM values were found to be relatively high and showed excellent correlation with the CL int, HIM values. Subsequently, we determined the plasma concentrations of 9 CYP3A substrates (buspirone, carbamazepine, diazepam, felodipine, midazolam, nicardipine, nifedipine, saquinavir, and verapamil) in monkeys after an oral dose of 2 mg/kg with or without an oral dose of 5 mg/kg ketoconazole and calculated AUC (؉vehicle) /AUC (؉ketoconazole) , defined as F g, monkey(observed) ; we confirmed that the dose of ketoconazole inhibited only intestinal CYP3A metabolism by preliminary in vitro and in vivo experiments using ketoconazole. The F g, monkey(observed) was lower than the F g, human(observed) for most compounds, but moderate correlation was observed. Furthermore, using these data, we established a new methodology to estimate F g, human(predicted) more precisely on the basis of the assumption that intestinal physiological conditions other than intrinsic metabolic activity would be the same between monkeys and humans. In conclusion, the in vivo model using cynomolgus monkeys in this study is useful for prediction of intestinal first-pass metabolism by CYP3A in humans because it was able to predict F g, human of all nine compounds investigated.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Prediction of the Intestinal First-Pass Metabolism of CYP3A Substrates in Humans Using Cynomolgus Monkeys

Nishimuta¹,

Sato²,

Mizuki³

et al. 2010

Drug Metab Dispos

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“…Pooled liver and small intestinal microsomes from humans and monkeys were supplied by XenoTech, LLC (Lenexa, KS). Recombinant P450 enzymes, coexpressed in E. coli membranes with human NADPH-P450 reductase, were prepared as described previously (Yamazaki et al, 2002;Uno et al, 2007). Cryopreserved hepatocytes of two cynomolgus monkeys were obtained from Biopredic International (Rennes, France).…”

Section: Methodsmentioning

confidence: 99%

“…Several studies have demonstrated that monkeys are particularly useful in interspecies scaling for predicting human pharmacokinetics (Ward and Smith, 2004;Ward et al, 2005;Sakuda et al, 2006;Ogasawara et al, 2007). 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.…”

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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“…P450 4F forms have been identified in various species, including mice (P450 4F13, 4F14, 4F15, 4F16, 4F17, 4F18, 4F37, 4F39, and 4F40), rats (P450 4F1, 4F4, 4F5, 4F6, 4F17, 4F18, 4F37, and 4F40), pigs (P450 4F55), cynomolgus monkeys (P450 4F2, 4F3B, 4F11, and 4F12), rhesus monkeys (P450 4F8, 4F12, and 4F22), and orangutans (P450 4F11 and 4F12). In cynomolgus monkeys, P450 4F2, 4F3B, 4F11, and 4F12 mRNAs were expressed in livers, kidneys, and/or jejuna (Uno et al, 2007). Cynomolgus monkey P450 4F2, 4F3B, and 4F11 proteins heterologously expressed in Escherichia coli metabolized arachidonic acids .…”

Section: Introductionmentioning

confidence: 99%

A New Marmoset P450 4F12 Enzyme Expressed in Small Intestines and Livers Efficiently Metabolizes Antihistaminic Drug Ebastine

Uehara

Uno

Yuki

et al. 2016

Drug Metabolism and Disposition

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Common marmosets (Callithrix jacchus) are attracting attention as animal models in preclinical studies for drug development. However, cytochrome P450s (P450s), major drug-metabolizing enzymes, have not been fully identified and characterized in marmosets. In this study, based on the four novel P450 4F genes found on the marmoset genome, we successfully isolated P450 4F2, 4F3B, 4F11, and 4F12 cDNAs in marmoset livers. Deduced amino acid sequences of the four marmoset P450 4F forms exhibited high sequence identities (87%-93%) to the human and cynomolgus monkey P450 4F homologs. Marmoset P450 4F3B and 4F11 mRNAs were predominantly expressed in livers, whereas marmoset P450 4F2 and 4F12 mRNAs were highly expressed in small intestines and livers. Four marmoset P450 4F proteins heterologously expressed in Escherichia coli catalyzed the v-hydroxylation of leukotriene B 4 . In addition, marmoset P450 4F12 effectively catalyzed the hydroxylation of antiallergy drug ebastine, a human P450 2J/4F probe substrate. Ebastine hydroxylation activities by small intestine and liver microsomes from marmosets and cynomolgus monkeys showed greatly higher values than those of humans. Ebastine hydroxylation activities by marmoset and cynomolgus monkey small intestine microsomes were inhibited (approximately 60%) by anti-P450 4F antibodies, unlike human small intestine microsomes, suggesting that contribution of P450 4F enzymes for ebastine hydroxylation in the small intestine might be different between marmosets/ cynomolgus monkeys and humans. These results indicated that marmoset P450 4F2, 4F3B, 4F11, and 4F12 were expressed in livers and/or small intestines and were functional in the metabolism of endogenous and exogenous compounds, similar to those of cynomolgus monkeys and humans.

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Characterization of cynomolgus monkey cytochrome P450 (CYP) cDNAs: Is CYP2C76 the only monkey-specific CYP gene responsible for species differences in drug metabolism?

Cited by 66 publications

References 25 publications

Prediction of the Intestinal First-Pass Metabolism of CYP3A Substrates in Humans Using Cynomolgus Monkeys

Prediction of the Intestinal First-Pass Metabolism of CYP3A Substrates in Humans Using Cynomolgus Monkeys

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

A New Marmoset P450 4F12 Enzyme Expressed in Small Intestines and Livers Efficiently Metabolizes Antihistaminic Drug Ebastine

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