Received for publication May 29, 2007.
Revised October 8, 2007.
Accepted for publication October 9, 2007.

Investigation of regional mechanisms responsible for poor oral absorption in man of a modified release preparation of the -adrenoreceptor antagonist, UK-338,003: the rational use of ex vivo intestine to predict in vivo absorption

Abstract

Modified release (MR) formulations are used to enhance the safety and compliance of existing drugs by improving their pharmacokinetics. Predicting the likely success of MR formulations is often difficult prior to clinical studies. A systematic in vitro approach using mouse and human tissues was adopted to rationalise the in vivo pharmacokinetics of 9hr and 15hr MR formulations of an -adrenoreceptor antagonist, UK-338,003. Immediate release UK-338,003 was well absorbed in man consistent with moderate Caco-2 permeability. In contrast, 9hr and 15hr release formulations showed marked reductions in C_max (47.1% and 68.9%) and AUC_0-72 (32.6% and 54.0%). Colonic intubation resulted in an 81.3% and 73.8% reduction in C_max and AUC_0-72. Mechanistic studies in isolated mouse tissues showed colonic UK-338,003 permeability (Papp <0.5 x 10^-6 cm/sec) was at least 40 times lower than ileum with marked asymmetry. UK-338,003 was found to be a substrate for PGP with a weaker interaction for MRP-type transporters in mouse intestine. PGP inhibition dramatically increased colonic UK-338,003 permeability to the levels observed in ileum. Low UK-338,003 A-B permeability was also observed in ex vivo human distal intestine but both the asymmetry and increase in permeability following PGP inhibition were significantly lower. In conclusion, the poor absorption of MR UK-338,003 in man can be explained by a combination of PGP-dependent efflux and low intrinsic permeability in the lower bowel. Regional permeability studies in ex vivo tissues employed during drug development can highlight absorption problems in the distal bowel and assess the feasibility of developing successful MR formulations.

Key words: ABC transporters, absorption, controlled drug release, drug delivery, intestinal transport, permeability, p-glycoprotein