Pharmacokinetics and metabolism of a sulphamide NK2 antagonist in rat, dogand human

1. UK-224,671 is a sulphamide-containing NK2 antagonist with moderate lipop hilicity and basicity. 2. The physicochemical properties of UK-224,671 are reflected in its pharma cokinetics following intravenous (i.v.) administration. The compound partit ioned extensively into red blood cells in all species examined and the bloo d clearance was moderate to low with respect to liver blood flow and distri bution 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 un changed UK-224,671 in both urine and faeces. In addition, of three metaboli tes observed, the most abundant was the N-descyclopropylmethyl (UK-280,045) . 5. The profile of radioactivity in rat following oral administration of [C- 14]-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 permea bility and extensive first-pass metabolism by the gut and does not result f rom poor gastrointestinal absorption per se.