The kinetics of 14C-GR43175 in rat and dog.
GR43175 is a selective 5-HT 1-like receptor agonist which is effective in the acute treatment of migraine. Rats and dogs were dosed intravenously (iv) and orally (po) with 1 mg 14C-GR43175 base (as succinate salt)/kg bodyweight. GR43175 is rapidly absorbed after oral dosing. In dog, 95-100% of the dose is absorbed, but less (25-30%) is absorbed by the rat. The bioavailability is greater than 54% in dog, but lower in rat. Except for the CNS, drug-related material is widely distributed after iv dosing, but is mainly concentrated in the gastrointestinal tract and excretory organs after oral dosing. GR43175 is eliminated from plasma by a combination of renal and metabolic clearance. Some first-pass metabolism occurs in both species. In dog the major route of excretion is in urine (78-83% of the dose) after either route of administration. In rat, urine is also the major route of excretion (71%) after iv dosing. After oral dosing to the rat the major route of excretion is in the faeces (83%). GR43175 is extensively metabolized, after either route of administration, in both species. GR49336, the indole acetic acid derivative of GR43175, is the major metabolite in dog and a major metabolite in rat.
Dallas
F A
FA
Glaxo Group Research Limited, Ware, Hertfordshire.
Dixon
C M
CM
McCulloch
R J
RJ
Saynor
D A
DA
D000284:Administration, Oral; D000818:Animals; D001345:Autoradiography; D004285:Dogs; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D051381:Rats; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018170:Sumatriptan; D014018:Tissue Distribution
D007211:Indoles; D013449:Sulfonamides; D018170:Sumatriptan