Correlation of Lipophilicity Descriptors with Pharmacokinetic Parameters of Selected Benzodiazepines

Abstract

In early-stage drug discovery science, it is often important to reliably predict the absorption, distribution, metabolism and 
elimination (ADME) property of new chemical entities in pipeline, in order to filter molecules that are not drug-like. Several invitro models of lipophilicity profiling as predictor of ADME property have been developed. The validity of lipophilicity 
determination based on different descriptors was evaluated using 4 model compounds of the benzodiazepine class; bromazepam, 
clonazepam, diazepam and lorazepam. Lipophilicity descriptors describing the retention behaviours of the model compounds 
were obtained from three approaches, namely; planar chromatographic determination (i.e. Isocratic chromatographic 
hydrophobicity index), calculated log P values (i.e. clog P, ChemAxon), and octanol-water partition coefficient (i.e. log P). These 
descriptors were correlated with in-vivo pharmacokinetic parameters - maximum plasma concentration (Cmax), time to reach peak 
plasma concentration (Tmax) and area under plasma concentration – time curve (AUC), using the Pearson rank correlation. The 
experimental approaches ranked diazepam as most lipophilic while in-silico approach ranked lorazepam as most lipophilic. AUC 
and Cmax correlated positively with the lipophilicity descriptors while Tmax gave negative correlation (except for the in-silico 
method) (r = 0.60, -0.74, and -0.25) with lipophilicity descriptors clog P, ICHI and logP respectively. ICHI gave the best 
correlation with pharmacokinetic parameters - Cmax (r = 1.0), AUC (r = 0.89) and Tmax (r = -0.74) The planar chromatographic 
platform was shown to be a valid biomembrane model for lipophilicity profiling. The lipophilicity descriptor, ICHI is positively 
and strongly correlated with Cmax, and found superior to the correlation of Cmax with time-honoured octanol/water log P. A larger 
study is thus warranted to delineate the potential of ICHI for general utility