Pharmacokinetics of the anti-leishmanian agent WR 6026 in dogs.
The pharmacokinetics of the anti-leishmanial agent WR 6026 (8-(6-diethylaminohexylamino)-6-methoxy-4-methylquinoline dihydrochloride) has been studied after single intravenous infusion and oral doses of 5 mg (base)/kg to 6 Beagle dogs. After single intravenous infusions of 15 min, plasma concentrations of unchanged drug declined bi-exponentially from a mean maximum of 1203 ng/ml +/- 277 SD at the end of infusion to the limit of quantitation during 16 hours. After single oral doses, the mean Cmax of 23 ng/ml +/- 14 SD occurred at a mean Tmax of 2.2 hours +/- 1.3 SD. During 72 hours after the intravenous and oral doses, 0.6% and less than 0.2% of the dose respectively was excreted unchanged in the urine. The mean terminal-life of WR 6026 after the infusion doses was +/- 0.3 SD, but after the oral doses, plasma concentrations of drug were too low to allow estimation of the terminal half-life. The systemic clearance of WR 6026 (43.5 ml/min/kg) greatly exceeded the nomina, plasma flow (ca. 22 ml/min/kg) and indicated considerable extra-hepatic and extra-renal elimination of WR 6026 in dogs. The mean systemic availability of WR 6026 after the oral doses was ca.4%. The mean volumes of distribution of WR 6026 in dogs were 3.3 litres/kg +/- 1.1 SD (V(ss)) and 7.7 litres/kg +/- 2.4 SD (V(area)). These data characterise WR 6026 as a drug of relatively high systemic clearance, large volume of distribution, relatively short half-life and low systemic availability, probably due to presystematic elimination in the liver.
Taylor
T
T
Department of Metabolism & Pharmacokinetics, Huntingdon Research Centre Ltd., England.
Hawkins
D R
DR
Morris
G R
GR
Chung
H
H
D000284:Administration, Oral; D000634:Aminoquinolines / Q000493:pharmacokinetics*; D000818:Animals; D000981:Antiprotozoal Agents / Q000493:pharmacokinetics*; D004032:Diet; D004285:Dogs; D006207:Half-Life; D007262:Infusions, Intravenous; D007891:Leishmania / Q000187:drug effects*; D008954:Models, Biological
D000634:Aminoquinolines; D000981:Antiprotozoal Agents; C080436:8-aminoquinoline