Pharmacokinetics of the active metabolite (MDL 74,156) of dolasetron mesylate after oral or intravenous administration to anesthetized children

Background : Dolasetron mesylate is a selective 5-HT 3 receptor antagonist under investigation as an antiemetic in children. Published studies indicate that its antiemetic activity results from the active metabolite (MDL 74,156), which is produced within 10 minutes of administration of dolasetron mesylate. Methods : The pharmacokinetics of MDL 74,156 and the safety and tolerability of dolasetron mesylate were studied after a single oral or intravenous dose of 1.2 mg.kg -1 dolasetron mesylate to healthy children from 2 to 12 years of age. Oral dolasetron was administered to 12 children 1 to 2 hours before anesthesia. Intravenous dolasetron was administered to 18 children at induction of anesthesia. Serial blood samples were collected for 24 hours after dosing to measure the plasma concentration of MDL 74,156. Indexes of liver and kidney function were determined, and electrocardiograms and adverse events were recorded. Results : Mean ± SD apparent plasma clearance of MDL 74,156 was 22.17 ± 9.33 and 13.17 ± 6.17 ml.min -1 .kg -1 and elimination half-life values were 5.7 ± 1.2 and 4.8 ± 1.1 hours after oral and intravenous doses, respectively. When normalized for body surface area, mean plasma clearance was 578.3 ± 232.5 and 331.67 ± 153.3 ml.min -1 .m -2 after oral and intravenous administration, respectively. Mean ± SD apparent volume of distribution at steady state after intravenous administration was 5.2 ± 2.2 L kg -1 or, when normalized for body surface area, 133.7 ± 55.8 L m -2 . Oral bioavailability was estimated to be 59%. There were no serious adverse events attributable to dolasetron mesylate or its metabolite. Conclusions : We found that the pharmacokinetics of MDL 74,156 were similar after both oral and intravenous administration of dolasetron to anesthetized children. Dolasetron mesylate appears to be safe and well tolerated in anesthetized children.