The species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humans

Takahashi, Masayuki; Washio, Takuo; Suzuki, Norio; Igeta, Katsuhiro; Yamashita, Shinji

doi:10.1002/jps.21708

Cited by 47 publications

(48 citation statements)

References 45 publications

(40 reference statements)

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“…Monkeys are widely used in preclinical studies to predict bioavailability (BA) in humans; however, they occasionally show a poorer BA than humans (Chiou and Buehler, 2002;Takahashi et al, 2009;Akabane et al, 2010). Among the reported poor-BA compounds were amitriptyline, nifedipine, and imipramine, which were found as CYP2C76 substrates in this study (Fig.…”

Section: Discussionmentioning

confidence: 82%

Evaluation of 89 Compounds for Identification of Substrates for Cynomolgus Monkey CYP2C76, a New Bupropion/Nifedipine Oxidase

et al. 2014

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Cynomolgus monkeys are widely used in preclinical studies during drug development because of their evolutionary closeness to humans, including their cytochrome P450s (P450s). Most cynomolgus monkey P450s are almost identical ( ‡90%) to human P450s; however, CYP2C76 has low sequence identity (approximately 80%) to any human CYP2Cs. Although CYP2C76 has no ortholog in humans and is partly responsible for species differences in drug metabolism between cynomolgus monkeys and humans, a broad evaluation of potential substrates for CYP2C76 has not yet been conducted. In this study, a screening of 89 marketed compounds, including human CYP2C and non-CYP2C substrates or inhibitors, was conducted to find potential CYP2C76 substrates. Among the compounds screened, 19 chemicals were identified as substrates for CYP2C76, including substrates for human CYP1A2 (7-ethoxyresorufin), CYP2B6 (bupropion), CYP2D6 (dextromethorphan), and CYP3A4/5 (dextromethorphan and nifedipine), and inhibitors for CYP2B6 (sertraline, clopidogrel, and ticlopidine), CYP2C8 (quercetin), CYP2C19 (ticlopidine and nootkatone), and CYP3A4/5 (troleandomycin). CYP2C76 metabolized a wide variety of the compounds with diverse structures. Among them, bupropion and nifedipine showed high selectivity to CYP2C76. As for nifedipine, CYP2C76 formed methylhydroxylated nifedipine, which was not produced by monkey CYP2C9, CYP2C19, or CYP3A4, as identified by mass spectrometry and estimated by a molecular docking simulation. This unique oxidative metabolite formation of nifedipine could be one of the selective marker reactions of CYP2C76 among the major CYP2Cs and CYP3As tested. These results suggest that monkey CYP2C76 contributes to bupropion hydroxylation and formation of different nifedipine oxidative metabolites as a result of its relatively large substrate cavity.

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Section: Discussionmentioning

confidence: 82%

Evaluation of 89 Compounds for Identification of Substrates for Cynomolgus Monkey CYP2C76, a New Bupropion/Nifedipine Oxidase

et al. 2014

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“…Additional studies using recombinant P450 enzymes supported remarkable differences in the metabolic activity between substrates (data not shown). This result may account for the moderate bioavailability of APZ in monkeys (50%), whereas several other CYP3A substrates undergo extensive first-pass metabolism (Takahashi et al, 2009). RIF treatment significantly increased CL tot and E H values of APZ (Table 4; Fig.…”

Section: Discussionmentioning

confidence: 96%

“…A recent study suggested that species differences could be mostly attributed not only to hepatic first-pass metabolism but also to the intestinal absorption process (Komura and Iwaki, 2008;Takahashi et al, 2009;Akabane et al, 2010). For example, minimal oral bioavailability of MDZ in cynomolgus monkeys (2-7%) is not fully explained by hepatic availability (ϳ70%) but is rather attributed to its low intestinal availability (ϳ10%) (Kanazu et al, 2004;Sakuda et al, 2006;Nishimura et al, 2007b;Ogasawara et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…However, the study failed to detect any increase in total clearance of MDZ after intravenous administration, because its hepatic clearance was close to the hepatic blood flow rate in monkeys. Monkeys also show poor oral bioavailability for other CYP3A substrates such as verapamil (ϳ1%), nifedipine (ϳ1%), methotrexate (8%), and simvastatin (0.8%), which are therefore not well suited for in vivo enzyme induction study (Ogasawara et al, 2009b;Takahashi et al, 2009). In addition, CYP3A is known to be induced in the small intestine as well as in the liver, and clinical studies have shown that repeated oral administration of representative CYP3A inducers, such as RIF and St. John's wort, resulted in the up-regulation of CYP3A expression in the small intestine (Tannergren et al, 2004;Glaeser et al, 2005) and increased intestinal first-pass metabolism of verapamil, another CYP3A substrate (Fromm et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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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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“…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). However, the oral bioavailability of some drugs, especially cytochrome P450 (P450) 3A4 substrates, is markedly lower in monkeys than humans (Takahashi et al, 2009), and it is often speculated that the cause is extensive first-pass metabolism in the monkey intestine (Sakuda et al, 2006;Nishimura et al, 2007;Ogasawara et al, 2007). Therefore, we anticipated that the prediction of intestinal first-pass metabolism in humans by in vivo methods using monkeys would be improved by taking the species differences in intrinsic intestinal metabolic activities between monkeys and humans into account.…”

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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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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The species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humans

Cited by 47 publications

References 45 publications

Evaluation of 89 Compounds for Identification of Substrates for Cynomolgus Monkey CYP2C76, a New Bupropion/Nifedipine Oxidase

Evaluation of 89 Compounds for Identification of Substrates for Cynomolgus Monkey CYP2C76, a New Bupropion/Nifedipine Oxidase

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

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

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