Dose-independent pharmacokinetics of ondansetron in rats: contribution of hepatic and intestinal first-pass effects to low bioavailability.
The pharmacokinetic parameters of ondansetron were evaluated after its intravenous (at doses of 1, 4, 8 and 20 mg/kg) and oral (4, 8 and 20 mg/kg) administration to rats. The gastric, intestinal and hepatic first-pass effects of ondansetron were also evaluated after its intravenous, oral, intraportal, intragastric and intraduodenal administration at a dose of 8 mg/kg to rats. After intravenous and oral administration of ondansetron, the drug exhibits dose-independent pharmacokinetics in rats. After oral administration of ondansetron at a dose of 8 mg/kg, the unabsorbed fraction was 0.0158 of the dose, the extent of absolute oral bioavailability (F) value was 0.0407, and the hepatic and intestinal first-pass effects were 40.0% and 34.2% of the oral dose, respectively. The low F of ondansetron in rats was mainly due to considerable hepatic and intestinal first-pass effects. The lower F of ondansetron in rats (4.07%) than that in humans (62+/-15%) was mainly due to greater hepatic metabolism of the drug in rats. Ondansetron was stable in the rat gastric juices and various buffer solutions having pHs ranging from 1 to 13. The equilibrium plasma-to-blood cells partition ratio of ondansetron was 1.74-5.31. Protein binding of ondansetron to fresh rat plasma was 53.2%.
Yang
Si H
SH
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
Lee
Myung G
MG
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005750:Gastric Juice / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D017294:Ondansetron / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*
D012702:Serotonin Antagonists; D017294:Ondansetron