Drug metabolism and disposition : the biological fate of chemicals
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Drug Metab. Dispos. · Feb 2013
Comparative StudyPrediction of crizotinib-midazolam interaction using the Simcyp population-based simulator: comparison of CYP3A time-dependent inhibition between human liver microsomes versus hepatocytes.
Crizotinib (Xalkori) is an orally available potent inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase and mesenchymal-epithelial transition factor. Objectives of the present study were as follows: 1) to characterize crizotinib time-dependent inhibition (TDI) potency for CYP3A in human liver microsomes (HLM) and cryopreserved human hepatocytes suspended in human plasma (HSP); 2) to characterize crizotinib enzyme induction potency on CYP3A4 in cryopreserved human hepatocytes; 3) to predict crizotinib steady-state plasma concentrations in patients (e.g., autoinhibition and autoinduction) using the mechanistic dynamic model, Simcyp population-based simulator; and 4) to predict a clinical crizotinib-midazolam interaction using the dynamic model as well as the static mathematical model. Crizotinib inactivation constant (K(I)) and maximum inactivation rate constant (k(inact)) for TDI were estimated as, respectively, 0.37 µM and 6.9 h(-1) in HLM and 0.89 µM and 0.78 h(-1) in HSP. ⋯ Based on these in vitro parameters, the predicted crizotinib steady-state area under plasma concentration-time curve (AUC) with HLM-TDI was 2.1-fold higher than the observed AUC, whereas that with HSP-TDI was consistent with the observed result (≤1.1-fold). The increase in midazolam AUC with coadministration of crizotinib (21-fold) was significantly overpredicted using HLM-TDI, whereas the prediction using HSP-TDI (3.6-fold) was consistent with the observed result (3.7-fold). Collectively, the present study demonstrated the value of HSP to predict in vivo CYP3A-mediated drug-drug interaction.
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Drug Metab. Dispos. · Feb 2013
Comparative StudyQuantitative prediction of CYP2B6 induction by estradiol during pregnancy: potential explanation for increased methadone clearance during pregnancy.
There is considerable evidence that pregnancy changes the disposition of drugs in an enzyme- and gestational stage-specific manner. On the basis of probe drug studies, the activity of CYP3A4 and CYP2D6 increases and CYP1A2 decreases during human pregnancy. However, no studies of CYP2B6 activity during human pregnancy have been conducted. ⋯ When the E(max) and EC(50) values were compared with those for carbamazepine and rifampin, estradiol was found to be as potent an inducer of CYP2B6 as rifampin and carbamazepine. These data suggest that, during human pregnancy, the increasing estradiol concentrations will result in increased clearance of drugs that have CYP2B6-mediated clearance pathways. This could in part explain the observed increase in methadone clearance during pregnancy.