Ondansetron pharmacokinetics

Pritchard JF, Bryson JC, Kernodle AE, Benedetti TL, Powell JR. Age and gender effects on ondansetron pharmacokinetics Evaluation of healthy aged volunteers. Clin Pharmacol Ther 1992 51 51-5. 

S.S. Siu, M.T. Chan, and T.K. Lau. Placental transfer of ondansetron during early human pregnancy. Clin Pharmacokinet. 45 419-423 (2006). 

The pharmacokinetics and metabolism of ondansetron will first be considered in rat and dog, the major species used in safety evaluation of the compound Table 7.7). Comparison will then be made with the available information on the pharmacokinetics of ondansetron in man. 

Table 7.7. A SUMMARY OF THE PHARMACOKINETIC PARAMETERS OF ONDANSETRON IN ANIMALS...

The pharmacokinetics of ondansetron in man have been determined in healthy volunteers after single and repeat doses [84]. The clinical pharmacokinetics (Table 7.8) showed many similarities with the kinetics in animals, but also some important differences. Elimination is rapid, but less so than in animals. The volume of distribution is similar in animals and man. As in animals, the clearance of ondansetron in man is predominantly by metabolism. However, metabolic clearance in man is considerably lower than in animals, resulting in a lower first-pass metabolism and a significantly greater oral bioavailability of 60 %. Steady-state concentrations of ondansetron are consistent with the single-dose kinetics of the compound and show no evidence of significant accumulation. 

Pharmacokinetics The elimination half-lives of these drugs range from 4 to 8 hours. Elimination is primarily via hepatic metabolism. Plasma concentrations of alosetron are 30% to 50% lower and less variable in men compared with women given the same dose. Plasma protein binding is 82% for alosetron, 65% for granisetron and 70% to 76% for ondansetron. The terminal elimination half-life of alosetron is approximately 1.5 hours. 

Figg WD, Dukes GE, Pritchard JF, et al. (1996) Pharmacokinetics of ondansetron in patients with hepatic insufficiency. Clin Pharmacol 36 206-215. 

Cox EH, Veyrat-FoIIet C, Beal SL, Fuseau E, Kenkare S, Sheiner LB. A population pharmacokinetic-pharmacodynamic analysis of repeated measures time-to-event pharmacodynamic responses The antiemetic effect of ondansetron. J Pharmacokinet Biopharm 1999 27 625M4. 

Example Ondansetron (Zofran) Route Pregnancy Pharmacokinetic Readily... 

De Alwis, D.P., Aarons, L., and Palmer, J.L. Population pharmacokinetics of ondansetron A covariate analysis. British Journal of Clinical Pharmacology 1998 46 117-125. 

Colthup, P.V. Palmer, J.L. The determination in plasma and pharmacokinetics of ondansetron. EurJ.Cancer Clin.Oncol., 1989, 25 Suppl 1, S71-S74... 

The 5-HT -receptor antagonists are the most widely used drugs for chemotherapy-induced emesis. Ondansetron (zofran) is the prototypical drug in this class other agents include granisetron (kytril), dolasetron (anzemet), palonosetron (aloxi intravenous use only) and tropisetron (available in some countries but not in the U.S.). Differences among these agents relate mainly to their chemical structures, 5-HTj receptor affinities, and pharmacokinetic profiles (Table 37-8). 

Ondansetron is a chiral antiemetic drug used to prevent nausea and vomiting associated with use of antineoplastics. Although chiral assays have been developed for the drug [228,229], in our search we could not find any literature that described the pharmacokinetic properties of the enantiomers of the drug in humans. 

A double-blind, placebo-controlled study in 12 healthy subjects found that a single 16-mg intravenous dose of ondansetron given 30 minutes after a single 10-mg intravenous dose of morphine did not alter the pharmacokinetics of morphine or its metabolites, morphine-3- and morphine-6-glu-curonides. The analgesic eifect of morphine (as measured by a contact thermode system) was also unaffected by ondansetron. ... 

Crews KR, Murthy BP, Hussey EK, Passannante AN, Palmer JL, Maixner W, Brouwer KLR Lack of effect of ondansetron on the pharmacokinetics and analgesic effects of morphine and metabolites after single-dose morphine administration in healthy volunteers. BrJClin Phar-macol (2001)51, 309-16. 

A placebo-controlled, crossover study in 26 healthy subjects found that both intravenous granisetron 3 mg and tropisetron 5 mg blocked the analgesic effect of a single 1 oral dose of paracetamol given 90 minutes later. The pharmacokinetics of paracetamol were unaffected by the two drugs. The interaction was thought to involve the serotonergic system, see Mechanism, in Opioids + Antiemetics Ondansetron , p.l61. 

Some evidence su ests ondansetron may modestly affect the pharmacokinetics of cyclophosphamide and cisplatin but it does not appear to affect those of carmustine. Ondansetron did not affect the in vitro activity of epirubicin, bleomycin, cisplatin or es-tramustine. Cisplatin and fluorouracil do not affect the pharmacokinetics of ondansetron. In in vitro studies granisetron potentiated the cytotoxic effects of epirubicin, had an additive effect on bleomycin and estramustine activity and appeared not to affect the metabolism of docetaxel and paclitaxel. 

The pharmacokinetics of high-dose cyclophosphamide, cisplatin and carmustine in 23 patients given ondansetron, lorazepam and diphenhydramine as antiemetics were compared with those in 129 patients who received prochlorperazine instead of ondansetron. It was found that the AUCs of cyclophosphamide and cisplatin, but not that of carmustine, were significantly lower (by 15% and 19%, respectively) in the ondansetron group. Similarly, in another study, the pharmacokinetics of antineoplastics were analysed in 54 patients with breast cancer who were receiving high-dose cyclophosphamide, cisplatin and carmustine with lorazepam and ondansetron with or without prochlorperazine and com-... 

Gilbert CJ, Petros WP, Vredenburgh J, Hussein A, Ross M, Rubin P, Fehdrau R, Cavanaugh C, Berry D, McKinstry C, Peters WP. Pharmacokinetic interaction between ondansetron and cyclophosphamide during high-dose chemotherapy for breast cancer. Cancer Chemoffier Pharmacol (1998) 42,497-503. 

The manufacturer notes that concurrent use of carbamazepine, dexamethasone, H2-receptor antagonists, ondansetron, phenobarbital, phenytoin or prochlorperazine did not affect the clearance of temozolomide, based on an analysis of population pharmacokinetics from phase II studies. However, valproic acid modestly reduced the clearance of temozolomide. 

In a placebo-controlled, crossover study in 24 healthy subjects ondansetron 8 mg did not affect the pharmacokinetics of temazepam 20 mg. The psychomotor performances ofthe subjects (subjective and objective sedation, memory and other measurements) were not influeneed by the presence of the ondansetron. ... 

Aprepitant had no clinically relevant effect on the pharmacokinetics of dolasetron, granisetron, ondansetron or palonosetron. 

No important pharmacokinetic interactions occur, therefore no dosage adjustment is required when aprepitant is given with dolasetron, ondansetron, granisetron or palonosetron. 

Blum RA, Majumdar A, McCrea J, Busillo J, Orlowski LH, Panebianco D, Hesney M, Petty KJ, Goldberg MR, Murphy MG, Gottesdiener KM, Hustad CM, Lates C, Kraft WK, Van Bu-ren S, Waldman SA, Greenberg HE. Effects of aprepitant on the pharmacokinetics of ondansetron and granisetron in healthy subjects. Clin Ther (2003) 25, 1407-19. 

Pharmacokinetic profile was compared with ondansetron conventional gel and oral marketed syrup. Bioavailability from miCToemulsion was found to be 6.03 folds more than oral conventional symp and 9.66 times more than OCG gel. 

Colthup, P.V. Palmer, J.L. The determination in plasma and pharmacokinetics of ondansetron. 

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