title: The role of P-glycoprotein in determining the oral absorption and clearance of the NK2 antagonist, UK-224,671.
abstract: 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.
authors: Department of Drug Metabolism, Pfizer Global Research and Development, Kent CT13 9NJ, Sandwich, UK. kevin_beaumont@pfizer.sandwich.com
authors: K
authors: K
authors: Beaumont
authors: A
authors: A
authors: Harper
authors: D A
authors: DA
authors: Smith
authors: J
authors: J
authors: Bennett
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001384:Azetidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D002460:Cell Line; D002463:Cell Membrane Permeability; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007413:Intestinal Mucosa; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*
chemical_list: C416764:4-(1-(2-(1-(cyclopropylmethyl)-3-(3,4-dichlorophenyl)-6-oxo-3-piperidyl)ethyl)azetidin-3-yl)-1-piperazine sulfamide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001384:Azetidines; D010879:Piperazines; D018041:Receptors, Neurokinin-2