Postoperative Nausea and Vomiting in Adults: PHARMACOKINETICS AND PHARMACODYNAMICS
Table 1 presents a summary of the pharmacokinetic and pharmacodynamic properties of ondansetron, granisetron canadian, and dolasetron.
Ondansetron
Ondansetron tablet was the first selective serotonin receptor antagonist to be marketed. It is administered both orally and parenterally. Following an oral dose, it is absorbed by the gastrointestinal (GI) tract and undergoes extensive hepatic metabolism, primarily hydroxylation, followed by glucuronide or sulfate conjugation.
The drug has an oral bioavailability of 56% to 71%, a rate that is slightly enhanced by the presence of food. Its elimination half-life is three to six hours in adults and two to three hours in children under 15 years of age. About 5% to 10% of the drug is excreted unchanged in the urine.
Table 1 Pharmacokinetic and Pharmacodynamic Properties of Ondansetron, Granisetron, and Dolasetron for Postoperative Nausea and Vomiting (PONV)
| Ondansetron (Zofran generic) | Granisetron (Kytril generic) | Dolasetron (Anzemet®) | |
| Drug
concentration levels |
Time to peak concentration is at end of the infusion after IV administration | Onset of initial response after IV administration is 4-I0 minutes with a duration of 24 hours | Average time to peak concentration is 0.6 hours after IV administration |
| Absorption | Has 56%-7l% mean oral bioavailability; absorption increases when it is given with food | Has 60% oral bioavailability | Has oral bioavailability of
59%-80%; no effect with food |
| Distribution | Has 70%-76% protein binding and a Vd of 2.2-2.5 L/kg | Has 65% total protein binding and is distributed widely throughout the body with a Vd of 2-4 L/kg | Hydrodolasetron is widely distributed in the body with a mean Vd of 5.8 L/kg in adults and 69%-77% protein binding |
| Metabolism | Undergoes extensive hepatic metabolism via hydroxylation, followed by glucuronide or sulfate conjugation | Undergoes extensive hepatic metabolism via N-demethyla-tion, oxidation, and conjugation | Undergoes reduction by a ubiquitous enzyme (carbonyl reductase) to an active metabolite (hydrodolasetron), which undergoes subsequent hydroxylation mediated by
CYP450, 2D6, and N-oxidation by CYP3A and flavin monooxygenase |
| Excretion | Renal excretion (44%-60% as metabolites, 5%-l0% as unchanged drug) and fecal excretion (25%) | Renal excretion (Il%-I2% as unchanged drug, 49% as metabolites) and fecal excretion (34%) | Urine (as unchanged drug) |
| Elimination half-life | 3-6 hours in adults; 2-3 hours in children younger than l5 years of age | I0-I2 hours in cancer patients; 4-5 hours in healthy volunteers;
9 hours in PONV |
Less than I0 minutes (parent compound) 4-9 hours (hydrodolasetron) |
| Dosage
adjustment: renal |
No dosing adjustment in renal impairment | No dosing adjustment in renal impairment | No dosing adjustment necessary in renal impairment |
| Dosage
adjustment: hepatic |
Clearance is reduced two-fold; mean half-life is increased to ll.6 hours in patients with mild-to-moderate hepatic impairment. Maximum daily dose of 8 mg in patients with severe liver disease | No dosing adjustment in hepatic impairment | No dosing adjustment necessary in hepatic impairment |
| Drug
interactions |
Substrate of CYPIA2 (minor), 2C8/9 (minor), 2D6 (minor), 2EI (minor), 3A4 (major)
Inhibits CYPlA2 (weak), 2C8/9 (weak), 2D6 (weak) |
Substrate of CYP3A4
(minor) |
Substrate of CYP2C8/9 (minor)
Inhibits CYP2D6 (weak) |
Potent inhibitors of cytochrome isozyme CYP1A2, 2D6, 2E1, and 3A4, such as cimetidine (Tagamet®, GlaxoSmithKline), allopurinol (Zyloprim®, Faro), generic ritonavir (Norvir drug, Abbott), and generic disulfiram (Antabuse tablet, Wyeth), may alter the metabolism and clearance of the drug, resulting in an elevated serum level of ondansetron canadian. Similarly, CYP1A2, 2D6, 2E1, and 3A4 induc-ers, such as rifampin, barbiturates, drug phenytoin (Dilantin generic, Pfizer), and the carbamazepines, can alter the clearance of the drug and decrease its serum level.
Granisetron
Granisetron medication is also administered orally and parenterally. When given with food, the total systemic exposure is decreased and the peak concentration is increased.
This drug is widely distributed in the body tissues and is approximately 65% protein-bound. It undergoes extensive hepatic metabolism, primarily by the CYP450 system, which
involves N-demethylation and aromatic ring oxidation, followed by conjugation. The elimination half-life varies according to the patient’s condition: for cancer patients, it is 10 to 12 hours; for healthy volunteers, it is 4 to 5 hours; and for those with PONV, it is 9 hours. Almost 12% of the dose is eliminated unchanged in the urine.
Granisetron is a substrate of CYP3A4. Enzyme inducers or inhibitors have the potential to affect the activity by decreasing or increasing the level of the drug.
Dolasetron
Dolasetron, available orally or parenterally, is well absorbed when taken orally. The parent drug is reduced completely to hydrodolasetron by a ubiquitous enzyme, carbonyl reductase. The apparent oral bioavailability determined by hydro-dolasetron is about 75% and is not affected by food.
Hydrodolasetron is distributed throughout the body and is 69% to 77% protein-bound. It undergoes subsequent hydroxylation by CYP2D6 and N-oxidation by CYP3A and flavin monooxygenase. Approximately two thirds of the dose is recovered in the urine, with one third recovered in the feces. The elimination half-life is less than 10 minutes for dolasetron and eight hours for hydrodolasetron.
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Administration of dolasetron with CYP450 inhibitors, such as cimetidine, can increase serum levels of hydrodolasetron. The serum level may be decreased when dolasetron is administered with CYP450 inducers such as rifampin.
Dolasetron has the potential to prolong the QT interval. Therefore, in patients receiving dolasetron, drugs that prolong the QT interval directly or those that alter the electrolytes should be used with caution.
