Application of a generic physiologically based pharmacokinetic model to the estimation of xenobiotic levels in rat plasma.
The routine assessment of xenobiotic in vivo kinetic behavior is currently dependent upon data obtained through animal experimentation, although in vitro surrogates for determining key absorption, distribution, metabolism, and elimination properties are available. Here we present a unique, generic, physiologically based pharmacokinetic (PBPK) model and demonstrate its application to the estimation of rat plasma pharmacokinetics, following intravenous dosing, from in vitro data alone. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature and validated using a separate test set of in vivo discovery compound data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was approximately 0.5 log unit. Around 70% of all the predicted values of a standardized measure of area under the concentration-time curve (AUC) were within 3-fold of the observed values, as were over 90% of the training set t1/2 predictions and 60% of those for the test set; however, there was a tendency to overpredict t1/2 for the test set compounds. The capability of the model to rank compounds according to a given criterion was also assessed: of the 25% of the test set compounds ranked by the model as having the largest values for AUC, 61% were correctly identified. These validation results lead us to conclude that the generic PBPK model is potentially a powerful and cost-effective tool for predicting the mammalian pharmacokinetics of a wide range of organic compounds, from readily available in vitro inputs only.
Brightman
F A
FA
Cyprotex Discovery Ltd., Macclesfield, Cheshire, United Kingdom, SK10 2DR.
Leahy
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DE
Searle
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GE
Thomas
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S
D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D003024:Clozapine / Q000097:blood / Q000493:pharmacokinetics; D004917:Erythromycin / Q000097:blood / Q000493:pharmacokinetics; D006207:Half-Life; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D023421:Models, Animal; D008954:Models, Biological; D015999:Multivariate Analysis; D010423:Pentazocine / Q000097:blood / Q000493:pharmacokinetics; D010672:Phenytoin / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D015203:Reproducibility of Results; D013997:Time Factors; D015262:Xenobiotics / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*
D015262:Xenobiotics; D010672:Phenytoin; D004917:Erythromycin; D003024:Clozapine; D010423:Pentazocine