UK-224671

UK-224,671 has been shown to exhibit low oral bioavailability in vivo due to poor absorption from the GI tract. The purpose of this study was to investigate the underlying reason for this observation. In Caco-2 cell flux experiments, the absorptive (A to B) flux of UK-224,671 was low, consistent with poor in vivo absorption. However, flux in the B to A direction was significantly greater, suggesting that UK-224,671 can permeate the membrane of the gut wall cell. Such a Caco-2 cell flux is indicative of transporter mediated efflux, possibly by P-glycoprotein. In P-glycoprotein knockout mice, the oral bioavailability of UK-224,671 was 22%, representing a significant increase over the P-glycoprotein expressing wild type mice (<2%). However, in the knockout mice absorption was still incomplete, suggesting that both P-glycoprotein mediated efflux and poor membrane permeation combine to limit the oral absorption of UK-224,671 in wild type mice. Lack of P-glycoprotein expression had no effect on the clearance of UK-224,671 in mice, which suggests that uptake from the blood into the excretory cell is mediated by a transporter other than P-glycoprotein. Bile duct cannulated rat experiments show that approximately 20% of the clearance of UK-224,671 occurs by direct secretion across the gut wall into the faeces. This clearance pathway requires UK-224,671 to cross both the basolateral and apical membranes of the gut wall cell. P-glycoprotein is likely to be involved in the passage of the compound across the apical membrane as has been observed for other P-glycoprotein substrates.

1. UK-224,671 is a sulphamide-containing NK2 antagonist with moderate lipophilicity and basicity. 2. The physicochemical properties of UK-224,671 are reflected in its pharmacokinetics following intravenous (i.v.) administration. The compound partitioned extensively into red blood cells in all species examined and the blood clearance was moderate to low with respect to liver blood flow and distribution into tissues was extensive. 3. UK-224,671 exhibited species differences in oral bioavailability. In dog, the compound exhibited moderate bioavailability (55%), whereas in rat and man oral bioavailability was < 10%. 4. In rat and dog, the major excreted form after i.v. administration was unchanged UK-224,671 in both urine and faeces. In addition, of three metabolites observed, the most abundant was the N-descyclopropylmethyl (UK-280,045). 5. The profile of radioactivity in rat following oral administration of [14C]-UK-224,671 was not consistent with a 10% absorbed compound with 40% of the dose present as metabolites. This suggests that the low bioavailability of UK-224,671 in rat is due to a combination of moderate intestinal permeability and extensive first-pass metabolism by the gut and does not result from poor gastrointestinal absorption per se.