Pharmacokinetics and metabolism of a sulphamide NK2 antagonist in rat, dog and human.
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.
Beaumont
K
K
Department of Drug Metabolism, Pfizer Central Research, Sandwich, UK. kevin_beaumont@sandwich.pfizer.com
Harper
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A
Smith
D A
DA
Abel
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D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000818:Animals; D001384:Azetidines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D002247:Carbon Isotopes; D002851:Chromatography, High Pressure Liquid; D003956:Dialysis; D004285:Dogs; D004912:Erythrocytes / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D015394:Molecular Structure; D010879:Piperazines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D010949:Plasma / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine
C416764:4-(1-(2-(1-(cyclopropylmethyl)-3-(3,4-dichlorophenyl)-6-oxo-3-piperidyl)ethyl)azetidin-3-yl)-1-piperazine sulfamide; D001384:Azetidines; D002247:Carbon Isotopes; D010879:Piperazines; D018041:Receptors, Neurokinin-2; D013449:Sulfonamides