Expanding LogP: Present possibilities

Abstract

Introduction: Due to the high candidate exclusion rate during a drug development process, an early prediction of the pharmacokinetic behavior would be needed. Accordingly, high performance bioaffinity chromatography (HPBAC) approaches are growing in popularity, however, there is a lack of knowledge and no consensus about the relation between HPBAC measurements, in vivo distribution and blood brain barrier (BBB) penetration behavior. With respect to radiotracers, there is almost no reference data available for plasma protein binding (PPB), permeability (Pm) and the membrane coefficient (K_IAM). Thus, this study was aimed at exploring the relevance of measuring PPB, Pm and K_IAM for the prediction of BBB penetration.

Methods: Measurements of %PPB, Pm and K_IAM were performed using HPBAC. In total, 113 compounds were tested, 43 with brain uptake, 30 not showing brain uptake and 40 with known interactions with efflux transporters. Additionally, ClogP and HPLC logP_ow^pH7.4 data were collected.

Results: %PPB, K_IAM, Pm and ClogP values were in the same range for each of the three groups. A significant difference was observed for the HPLC logP_ow^pH7.4 between CNS penetrating drug group (CNS_pos) and the non-penetrating drug group (CNS_neg), as well as for the CNS_neg towards the drug group interacting with efflux transporters (DRUG_efflux). However, as the other experimental data, also the HPLC logP_ow^pH7.4 showed a broad overlapping of the single values between the groupings.

Conclusion: Experimental reference values (logP, Pm, K_IAM & PPB) of commonly used PET tracers and drugs showing different BBB penetration behavior are provided. The influence of the logP on brain uptake depends strongly on the selected method. However, using a single parameter (experimental or calculated) to predict BBB penetration or for the classification of drug groups is inexpedient.

Keywords: Blood brain barrier (BBB); High performance bioaffinity chromatography (HPBAC); Membrane coefficient (K(IAM)); Permeability (Pm); Plasma protein binding (PPB).