Abstract

Two predictive tools have been proposed by Austin et al. (Drug Metab Dispos 30:1497–1503, 2002) and Hallifax and Houston (Drug Metab Dispos 34:724–726, 2006) to estimate the fraction unbound in the incubation (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 data set (n = 127) comprised 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 with 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 cutoff 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, irrespective of the microsomal protein concentration investigated.

By Michael Gertz, Peter J. Kilford, J. Brian Houston and Aleksandra Galetin