Structure-Based Prediction of the Nonspecific Binding of Drugs to Hepatic Microsomes
- 374 Downloads
For the accurate prediction of in vivo hepatic clearance or drug–drug interaction potential through in vitro microsomal metabolic data, it is essential to evaluate the fraction unbound in hepatic microsomal incubation media. Here, a structure-based in silico predictive model of the nonspecific binding (fumic, fraction unbound in hepatic microsomes) for 86 drugs was successfully developed based on seven selected molecular descriptors. The R 2 of the predicted and observed log((1 − fumic)/fumic) for the training set (n = 64) and test set (n = 22) were 0.82 and 0.85, respectively. The average fold error (AFE, calculated by fumic rather than log((1 − fumic)/fumic)) of the in silico model was 1.33 (n = 86). The predictive capability of fumic for neutral drugs compared well to that for basic compounds (R 2 = 0.82, AFE = 1.18 and fold error values were all below 2, except for felodipine and progesterone) in our model. This model appears to perform better for neutral compounds when compared to models previously published in the literature. Therefore, this in silico model may be used as an additional tool to estimate fumic and for predicting in vivo hepatic clearance and inhibition potential from in vitro hepatic microsomal studies.
Key wordsfraction unbound in hepatic microsomes in silico prediction molecular descriptors
We are thankful to Accelrys Inc. for providing 1-month free evaluation of TSAR software in 2007.
- 6.Uchaipichat V, Winner LK, Mackenzie PI, Elliot DJ, Williams JA, Miners JO. Quantitative prediction of in vivo inhibitory interactions involving glucuronidated drugs from in vitro data: the effect of fluconazole on zidovudine glucuronidation. Br J Clin Pharmacol 2006;61:427–39.PubMedCrossRefGoogle Scholar
- 15.Ghanbari F, Rowland-Yeo K, Bloomer JC, Clarke SE, Lennard MS, Tucker GT, Rostami-Hodjegan A. A critical evaluation of the experimental design of studies of mechanism based enzyme inhibition, with implications for in vitro-in vivo extrapolation. Curr Drug Metab 2006;7:315–34.PubMedCrossRefGoogle Scholar
- 21.TSAR. 3.3 Reference Guide, Oxford Molecular Limited, 2000.Google Scholar