Ondansetron metabolism

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. 

After either oral or intravenous administration of ondansetron to laboratory animals the elimination of the drug is rapid. The short elimination half-lives t ji Table 7.7) reflect the high plasma clearance (CLp) in these species. Renal clearance (CLr) is below glomerular filtration rate, indicating that the major component of systemic clearance is metabolism. Ondansetron is rapidly absorbed after oral administration, peak concentrations in plasma being achieved within 40 min of dosing. However, the oral bioavailability is low. The similarity between concentrations of total drug-related material in plasma after oral and intravenous doses indicates that the low... 

After either oral or intravenous administration of [ Cjondansetron to rats the majority (about 80 %) of the radioactive dose is voided in the faeces, the remainder of the dose being excreted in the urine. In the dog, faecal elimination accounts for about half of the dose and is independent of the route of administration. Evidence from animals with cannulated bile-ducts indicates that the major route of excretion is via the bile. In both species, less than 5 % of the dose is excreted unchanged in urine, suggesting that extensive metabolism of ondansetron occurs. 

The metabolites of ondansetron have been examined in urine and bile from rat and dog. The major pathways for metabolism of ondansetron are A-demethylation and hydroxylation Scheme 7.7). However, whereas A-de-methylation predominates in dog, this is only a minor metabolic route in rat. Hydroxylation may occur at the 6, 7 or 8 position in the carbazolone ring. Hydroxy metabolites of ondansetron are excreted predominantly as glucuronide or sulphate conjugates. Studies with immobilised glucuronyl-transferase (Heath, S.E., personal communication) have demonstrated that O- and A-glucuronidation of ondansetron metabolites may occur. 

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. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

Three agents are available ondansetron, granisetron, and dolasetron. The drugs have a long serum half-life of 4-9 hours and may be administered once or twice daily by oral or intravenous routes. The drugs undergo extensive hepatic metabolism and are eliminated by renal and hepatic excretion. However, dose reduction is not required in geriatric patients or patients with renal insufficiency. For patients with hepatic insufficiency, dose reduction may be required with ondansetron. 

All antiemetics are well absorbed from the gastrointestinal tract, with a C 3x of hours following an oral dose. Domperidone, granisetron, ondansetron, prochlorperazine and promethazine undergo extensive first-pass metabolism, which reduces bioavailability. 

Ondansetron may be the drug of choice in this patient as they are also suffering itch. As there is no change in the patient s metabolic function, a dose of 4-8 mg (50-100 pg/kg in children) two or three times daily could be used. Rifampicin may reduce the antiemetic effect. 

Ondansetron could be used, but the dose should be reduced to 4 mg once a day as this patient has very little metabolic and synthetic liver function. 

TCAs ANTIEMETICS-ONDANSETRON, TROPISETRON Possible t plasma concentrations of these antiemetics Inhibition of CYP2D6-mediated metabolism of these antiemetics. The clinical significance of this depends upon whether their alternative pathways of metabolism are also inhibited by co-administered drugs. The risk is theoretically higher with ondansetron because TCAs also inhibit CYP1 A2-mediated metabolism Warn patients to report T side-effects of ondansetron and tropisetron... 

ONDANSETRON, TROPISETRON ANTIBIOTICS - RIFAMPICIN 1 levels of these drugs Induction of metabolism Watch for poor response to ondansetron and tropisetron consider using an alternative antiemetic... 

ONDANSETRON CARBAMAZEPINE, PHENYTOIN Reports of 1 ondansetron levels Induction of metabolism of ondansetron Watch for poor response to ondansetron care with other 5-HT3 antagonists... 

ONDANSETRON CNS STIMULANTS -MODAFINIL May cause 1 ondansetron levels if CYP1A2 is the predominant metabolic pathway and alternative metabolic pathways are either genetically deficient or affected Modafinil is moderate inducer of CYP1A2 in a concentration-dependent manner Be aware... 

CANNABIS ANTI EMETICS -ONDANSETRON i levels, with risk of therapeutic failure Induction of CYP1A2-mediated metabolism by any form of smoking. Foods (e.g. broccoli, cabbage, Brussels sprouts, chargrilled meat) also induce this isoenzyme Watch for poor response to ondansetron conversely, watch for toxic effects if a previously heavy cannabis user stops smoking... 

Cyclophosphamide produces severe nausea and is often used with a 5HT3 antagonist, ondansetron. Cyclophosphamide is metabolized to a toxic metabolite called acrolein, which can cause haemorrhagic cystitis, a rare but serious complication. This effect can be counteracted by a high intake of fiuid and by using a drug called mesna. Otherwise,... 

Ondansetron is metabolized by cytochrome P450 thns, inducers or inhibitors of this enzyme may change the... 

Dixon, C.M. Colthup, P.V. Serabjit-Singh, C.J. Kerr, B.M. Boehlert, C.C. Park, G.R. Tarbit, M.H. Multiple forms of cytochrome P450 are involved in the metabolism of ondansetron in humans. Drug Metab.Dispos., 1995,23, 1225-1230... 

Fischer, V. Vickers, A.E.M. Heitz, F. Mahadevan, S. Baldeck, J.-P. Mineiy, P. lynes, R. The polymorphic C3dochrome P-4502D6 is involved in the metabolism of both 5-hydroxytryptamine antagonists, tropisetron and ondansetron. Drug Metab.Dispos., 1994,22, 269-274 [microsomal incubations human liver extracted metabolites gradient column temp 40 radioactivity detection]... 

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