Cambridge MedChem Consulting

Absorption

Deciding whether a drug is absorbed by Passive or Active-Transport

Passive transport

Data taken from (Kansy, M. et al. in Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical and Computational Strategies (eds Testa, B., Van de Waterbeemd, H., Folkers, G. & Guy, R.) 447-464 (Wiley-VCH, Zurich, 2001).)

Carrier-mediated transport

If the absorption is permeability limited Possibly due to efflux pump Can it be saturated at reasonable doses? If the absorption is solubility limited Look at formulations Poor solubility could be a liability in development, particularly if a new less soluble crystal form is identified. Improve solubility Reduce molecular weight, introduce ionisable groups, H-bonding groups, reduce LogP Prodrugs, Acyclovir is very poorly absorbed and a number of prodrugs have been developed to improve absorption and hence bioavailability. The examples below use active transport systems to increase uptake.

Assays

PAMPA

MDCK-hMDR1

Incubate with Lucifer yellow at the start to check integrity of membrane Papp should be < 10 nm/s. Always include an internal control, the assay can very from week to week.

In theory you should get 100% recovery from these sort of experiments, reduced recovery can mean binding to the plate of cell mono layer, or it can be due to poor solubility.

Updated 14 December 2015