Prediction of oral clearance from<i>in vitro</i>metabolic data using recombinant CYPs: Comparison among well-stirred, parallel-tube, distributed and dispersion models

Yamamoto, Takahiko; Itoga, Hiroki; Kohno, Yoshiro; Nagata, Kiyoshi; Yamazoe, Yasushi

doi:10.1080/00498250500159371

Cited by 17 publications

(11 citation statements)

References 29 publications

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“…Comparisons of the accuracy in the predictions among different mathematical models have been reported (10,21,79). Results indicated that the three models predicted hepatic clearance with equal levels of accuracy (10,21), while the predictions of in vivo metabolic clearance from in vitro data were comparable between "parallel-tube" and "dispersion" models, and both more accurate with less biased and higher precision than "well-stirred" model (21) or the "dispersion" model provided more reliable prediction for the highclearance drugs than the other models (20,(85)(86)(87). Fig.…”

Section: Limitation Of In Vitro Metabolic Clearance To Predict In Vivmentioning

confidence: 90%

“…Successful extrapolations of in vitro metabolic clearance obtained in the recombinant CYP isoforms to that in vivo have been well documented for the compounds with less significant contribution of hepatic uptake to overall clearance in human (115,(119)(120)(121). This approach cannot only provide quantitative information on the relative contribution of CYP isoform(s) involved in the metabolism of the compound of interest but also the preliminary prediction of hepatic clearance attributable to the CYP-mediated metabolism in human at discovery stage (87,116,122,123). Similar methods have been applied to the quantitative assessment for relative contribution of particular transporter to the overall uptake of the compound of interest in hepatocytes by using RAFs with the reference ligands such as taurocholate (124) and estradiol-17β-D-glucuronide (E 2 17βG) (125) to Ntcp and Oatp1a1, respectively.…”

Section: Prediction Of Tarnsporter-mediated Hepatic Uptake Clearance mentioning

confidence: 99%

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Prediction of Hepatic Clearance in Human From In Vitro Data for Successful Drug Development

Chiba

Ishii²,

Sugiyama

2009

AAPS J

192

168

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Abstract. The in vivo metabolic clearance in human has been successfully predicted by using in vitro data of metabolic stability in cryopreserved preparations of human hepatocytes. In the predictions by human hepatocytes, the systematic underpredictions of in vivo clearance have been commonly observed among different datasets. The regression-based scaling factor for the in vitro-to-in vivo extrapolation has mitigated discrepancy between in vitro prediction and in vivo observation. In addition to the elimination by metabolic degradation, the important roles of transporter-mediated hepatic uptake and canalicular excretion have been increasingly recognized as a rate-determining step in the hepatic clearance. It has been, therefore, proposed that the in vitro assessment should allow the evaluation of clearances for both transporter(s)-mediated uptake/excretion and metabolic degradation. This review first outlines the limited ability of subcellular fractions such as liver microsomes to predict hepatic clearance in vivo. It highlights the advantages of cryopreserved human hepatocytes as one of the versatile in vitro systems for the prediction of in vivo metabolic clearance in human at the early development stage. The following section discusses the mechanisms underlying the systematic underprediction of in vivo intrinsic clearance by hepatocytes. It leads to the proposal for the assessment of hepatic uptake clearance as one of the kinetically important determinants for accurate predictions of hepatic clearance in human. The judicious combination of advanced technologies and understandings for the drug disposition allows us to rationally optimize new chemical entities to the drug candidate with higher probability of success during the clinical development.

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Section: Limitation Of In Vitro Metabolic Clearance To Predict In Vivmentioning

confidence: 90%

Section: Prediction Of Tarnsporter-mediated Hepatic Uptake Clearance mentioning

confidence: 99%

Prediction of Hepatic Clearance in Human From In Vitro Data for Successful Drug Development

Chiba

Ishii²,

Sugiyama

2009

AAPS J

192

168

View full text Add to dashboard Cite

show abstract

“…(3b), respectively. The accuracy of the various models for predicting hepatic clearance should not be confused with the accuracy in predicting oral clearance, where differences between the models are accentuated by the term F h (fraction escaping hepatic metabolism) [43]. The human dataset has been published [7] and recently confirmed for a similar sized dataset using measurements within AstraZeneca (data not shown).…”

Section: Prediction Of Hepatic Metabolic Clearancementioning

confidence: 95%

The Impact of In Vitro Binding on In Vitro - In Vivo Extrapolations, Projections of Metabolic Clearance and Clinical Drug-Drug Interactions

Grime¹,

Riley²

2006

CDM

111

112

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This review provides a vista of the current opportunities and remaining challenges in the area of in vitro-in vivo extrapolation, with particular emphasis on drug binding terms in predictive models, which has been the source of much controversy. Although the importance of fu(inc) (fraction unbound in in vitro incubations) has been acknowledged for decades, it is not always applied in practice. This is somewhat disappointing, since although it may be onerous to measure this term for large numbers of compounds, algorithms to estimate the term from logD(7.4) or logP have been detailed in the literature. These are sufficiently robust to negate routine measurement in early drug discovery. Several groups have recently established convincing relationships between unbound in vivo and in vitro metabolic intrinsic clearance (CL(int)). In the authors' laboratory, correlations of this type have been constructed for rat, dog and Man. The use and interpretation of these models within a drug discovery setting is discussed. The quantitative prediction of drug-drug interactions from in vitro cytochrome P450 (CYP) inhibition data remains a challenge. Although extensive literature databases are at last emerging, apparent ad hoc use of terms for in vivo inhibitor concentrations and only occasional consideration of fu(inc) may only have confused matters. The effect of accounting for drug binding on the accuracy of predictions is reviewed. Other themes including the impact of fu(inc) on relative activity factors (RAFs) and how in vitro data quality and inter-laboratory differences can confound quantitative human pharmacokinetic predictions are also developed.

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“…Prediction of Hepatic Clearance. The hepatic clearance (CL h ) of erlotinib was predicted from CL int, app using the well-stirred liver model as follows (Witherow and Houston, 1999;Riley et al, 2005;Yamamoto et al, 2005),…”

Section: Methodsmentioning

confidence: 99%

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

et al. 2013

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Erlotinib is approved for the treatment of non-small cell lung and pancreatic cancers, and is metabolized by CYP3A4. Inducers and inhibitors of CYP3A enzymes such as ritonavir and efavirenz, respectively, may be used as part of the highly active antiretroviral therapy drugs to treat patients with human immunodeficiency virus (HIV). When HIV patients with a malignancy need treatment with erlotinib, there is a potential of as-yet-undefined drug-drug interaction. We evaluated these interactions using human hepatocytes benchmarked against the interaction of erlotinib with ketoconazole and rifampin, the archetype cytochrome P450 inhibitor and inducer, respectively. Hepatocytes were treated with vehicle [0.1% dimethylsulfoxide, ritonavir (10 mM)], ketoconazole (10 mM), efavirenz (10 mM), or rifampin (10 mM) for 4 days. On day 5, erlotinib (5 mM) was incubated with the above agents for another 24-48 hours. Concentrations of erlotinib and O-desmethyl erlotinib were quantitated in collected samples (combined lysate and medium) using liquid chromatography and tandem mass spectrometry. The half-life (t 1/2 ) of erlotinib increased from 10.6 6 2.6 to 153 6 80 and 23.9 6 4.8 hours, respectively, upon treatment with ritonavir and ketoconazole. The apparent intrinsic clearance (CL int, app ) of erlotinib was lowered 16-fold by ritonavir and 1.9-fold by ketoconazole. Efavirenz and rifampin decreased t 1/2 of erlotinib from 10.3 6 1.1 to 5.0 6 1.5 and 3.4 6 0.2 hours, respectively. Efavirenz and rifampin increased the CL int, app of erlotinib by 2.2-and 2-fold, respectively. Our results suggest that to achieve desired drug exposure, the clinically used dose (150 mg daily) of erlotinib may have to be significantly reduced (25 mg every other day) or increased (300 mg daily), respectively, when ritonavir or efavirenz is coadministered.

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Prediction of oral clearance fromin vitrometabolic data using recombinant CYPs: Comparison among well-stirred, parallel-tube, distributed and dispersion models

Cited by 17 publications

References 29 publications

Prediction of Hepatic Clearance in Human From In Vitro Data for Successful Drug Development

Prediction of Hepatic Clearance in Human From In Vitro Data for Successful Drug Development

The Impact of In Vitro Binding on In Vitro - In Vivo Extrapolations, Projections of Metabolic Clearance and Clinical Drug-Drug Interactions

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

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