<b><i>In vivo</i></b>approach for the evaluation of mechanism-based inhibition of cytochrome P450 3A in rats

Sekiguchi, Nobuo; Kato, Motohiro; Takada, Maiko; Watanabe, Hidenori; Higashida, Atsuko; Sakai, Shuichi; Ishigai, Masaki; Aso, Yoshinori

doi:10.1080/00498250701851891

Cited by 8 publications

(15 citation statements)

References 26 publications

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“…Therefore, we aimed to quantitatively predict the DDI observed in rats using a PBPK model from in vitro inactivation parameters in this study. Although it was suggested that MDZ was mainly metabolized by CYP3A in rats (Sekiguchi et al, 2008), not only CYP3A but also CYP2C isozymes were reported to produce metabolites of MDZ in rats (Chovan et al, 2007). Therefore, there is a possibility that CYP2C isozymes are also inactivated by mibefradil.…”

Section: Introductionmentioning

confidence: 98%

“…In addition, gastrointestinal absorption is assumed to be described by a first-order rate constant. Plasma concentrations of MDZ from the literature (Sekiguchi et al, 2008) and mibefradil measured by the procedure described above when they were administered solely (E act ϭ E 0 ) were fitted into the PBPK model described above, and CL int, S , CL int, I , k a, S , k a, I , V sys, S , and V sys, I were calculated using SAAM II (version 1.2; Saam Institute, Inc., Seattle, WA). The differential equation for E act can be described as follows (eq.…”

Section: Methodsmentioning

confidence: 99%

“…According to the literature, the dosing route and regimen for the DDI study of MDZ and mibefradil were scheduled as follows. Twenty-four hours after oral administration of mibefradil at 6 or 12 mg/kg, MDZ was administered orally at 10 mg/kg (Sekiguchi et al, 2008). Simulated …”

Section: Methodsmentioning

confidence: 99%

“…Only a few reports investigating MBI in animals have been published (Sekiguchi et al, 2008;Ogasawara et al, 2009). Demonstrating in vitro-in vivo extrapolation in animals seems to increase confidence in predictions of clinical DDIs from in vitro data with human tissues.…”

Section: Introductionmentioning

confidence: 99%

“…Demonstrating in vitro-in vivo extrapolation in animals seems to increase confidence in predictions of clinical DDIs from in vitro data with human tissues. We reported previously that after pretreatment with mibefradil, a mechanism-based inhibitor of CYP3A, at 6 and 12 mg/kg 24 h before the oral administration of midazolam (MDZ), a probe substrate, in rats, the C max and the area under the concentration-time curve (AUC) of MDZ were significantly elevated in comparison with the control (Sekiguchi et al, 2008). Therefore, we aimed to quantitatively predict the DDI observed in rats using a PBPK model from in vitro inactivation parameters in this study.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Prediction of Mechanism-Based Inhibition Caused by Mibefradil in Rats

Sekiguchi¹,

Kato²,

Takada³

et al. 2011

Drug Metab Dispos

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ABSTRACT:It was previously demonstrated that mibefradil, which shows mechanism-based inhibition in humans, also caused drug-drug interactions (DDIs) with midazolam (MDZ) in rats. In this study, we aimed to quantitatively predict the DDIs observed in rats using a physiologically based pharmacokinetic (PBPK) model from in vitro inactivation parameters. For more precise predictions, contribution ratios of cytochrome P450 (P450) isozymes involved in MDZ metabolism and inactivation parameters of mibefradil against each isozyme were incorporated in the predictive model. The evaluation of metabolic rate using recombinant P450s suggested that CYP3A2 and CYP2C11 contributed to 89 and 11% of MDZ metabolism, respectively. Inactivation studies of mibefradil against the two isozymes showed that the maximal inactivation rate constants (k inact ) were considerable in both isozymes (0.231-0.565 min ؊1 ), whereas the inhibitor concentration producing half the k inact (K I, app ) of CYP3A2 (0.263-0.410 M) was a good deal lower than that for CYP2C11 (6.82-11.4 M). As a result of predicting the DDIs using the PBPK model, predicted increases in areas under the concentration-time curve of MDZ with coadministration of mibefradil (284 and 510% at 6 and 12 mg/kg mibefradil, respectively) closely corresponded to the observed values (226 and 545%, respectively). From those results, it was thought that the construction of a predictive model for DDIs using the PBPK model in detail would enable us to quantitatively predict in vivo DDIs from in vitro data. This approach to predict DDIs on the basis of the contributing isozymes would be important for predicting clinical DDIs of drugs metabolized by multiple enzymes.

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Section: Introductionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Quantitative Prediction of Mechanism-Based Inhibition Caused by Mibefradil in Rats

Sekiguchi¹,

Kato²,

Takada³

et al. 2011

Drug Metab Dispos

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Investigation of drug–drug interaction via mechanism‐based inhibition of cytochrome P450 3A by macrolides in dexamethasone‐treated female rats

Kanazu

Satô

Kadono

et al. 2012

Biopharm & Drug Disp

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The in vitro and in vivo inhibition of cytochrome P450 (CYP) 3A with mechanism‐based inhibition (MBI) by macrolides was investigated using dexamethasone‐treated female rats (DEX‐female rats). In the in vitro CYP inhibition studies using erythromycin (ERM) and clarithromycin (CAM), similar inhibition responses were observed between human and DEX‐female rat liver microsomes, however, there were fewer effects in intact male rats. The ex vivo study showed that midazolam (MDZ) metabolism in liver microsomes of DEX‐female rats was reduced by ERM administration and the inhibitory effect was increased with increasing ERM doses, indicating that metabolite intermediate complex formation caused irreversible inhibition of CYP3A activity in DEX‐female rats as well as in humans. In the in vivo studies, ERM and CAM significantly increased the area under the plasma concentration–time curve of MDZ and decreased the total clearance in DEX‐female rats. It was concluded that the DDIs via MBI of CYP3A following macrolide administration in humans could be reproduced in female rats, suggesting that DEX‐female rats can serve as an in vivo model for assessing this DDI in humans. Copyright © 2012 John Wiley & Sons, Ltd.

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N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine (CP-100,356) as a “chemical knock-out equivalent” to assess the impact of efflux transporters on oral drug absorption in the rat

Kalgutkar¹,

Frederick²,

Chupka³

et al. 2009

Journal of Pharmaceutical Sciences

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In vivoapproach for the evaluation of mechanism-based inhibition of cytochrome P450 3A in rats

Cited by 8 publications

References 26 publications

Quantitative Prediction of Mechanism-Based Inhibition Caused by Mibefradil in Rats

Quantitative Prediction of Mechanism-Based Inhibition Caused by Mibefradil in Rats

Investigation of drug–drug interaction via mechanism‐based inhibition of cytochrome P450 3A by macrolides in dexamethasone‐treated female rats

N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine (CP-100,356) as a “chemical knock-out equivalent” to assess the impact of efflux transporters on oral drug absorption in the rat

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