Received for publication September 18, 2007.
Revised December 19, 2007.
Accepted for publication December 19, 2007.

Drug lipophilicity and microsomal protein concentration as determinants in the prediction of the fraction unbound in microsomal incubations

Abstract

Two predictive tools have been proposed by Austin et al. (Drug Metab Dispos 2002, 30: 1497-1503) and Hallifax and Houston (Drug Metab Dispos 2006, 34:724-726) to estimate microsomal nonspecific binding (fu_inc). The current study was undertaken to elucidate the relative utility of these prediction tools over a range of drug lipophilicity and microsomal protein concentration. The fu_inc dataset (n=127) comprised of 35 drugs determined experimentally in this study and 92 collated from Austin and Hallifax data. The observed fu_inc values at three microsomal concentrations were compared to the estimates obtained using the Austin and Hallifax equations. In addition, the impact of variability in the logP on the fu_inc predictions was assessed. The current analysis highlights the importance of accurate estimation of lipophilicity for the prediction of the fu_inc, regardless of the prediction equation used. Both equations represent useful tools for estimation of fu_inc for low lipophilicity drugs (logP/D = 0 - 3), especially at low microsomal protein concentration. However, the accuracy of fu_inc predictions of highly lipophilic drugs was poor for both equations, implying that fu_inc should be experimentally confirmed for drugs with logP/D 3 unless the microsomal protein concentration is as low as 0.1 mg/mL in which case a cut-off of logP/D 5 can be applied. A significant difference in the predictions by the two proposed tools was observed in the area of intermediate lipophilicity (logP/D = 2.5 - 5) where the Hallifax equation provided more accurate fu_inc predictions on average and irrespective of the microsomal protein concentration investigated.

Key words: drug clearance, in vitro-in vivo scaling, microsomes, protein binding

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