known to cause QT prolongation with potential for torsades de pointes including dolasetron.
PREGNANCY AND LACTATION
Pregnancy
Dolasetron has been classified as FDA pregnancy risk category B. Animal studies have not revealed any teratogenic effects associated with dolasetron. There are no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Other alternatives exist. The American College of Obstetricians and Gynecologists recommends the use of ondansetron for the treatment of nausea and vomiting of pregnancy in patients who are dehydrated, requiring IV fluid replacement, and have failed other therapies.
According to the manufacturer, it is not known whether dolasetron is excreted in human milk. However, because of its low molecular weight, transfer into breast milk should be expected. Caution should be exercised when administering dolasetron to a breast-feeding woman. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
MECHANISM OF ACTION
Dolasetron and its active metabolite, hydrodolasetron, selectively block type 3 serotonin (5-HT3) receptors. 5-HT3 receptors are found centrally in the chemoreceptor trigger zone and peripherally at vagal nerve terminals in the intestines. Whether the action of dolasetron is mediated centrally, peripherally, or a combination of both remains to be determined. Nausea and vomiting during chemotherapy appears to be associated with the release of serotonin from enterochromaffin cells in the small intestine. Blocking these nerve endings in the intestines prevents signals to the central nervous system.
PHARMACOKINETICS
Dolasetron is administered intravenously or orally. Once in the systemic circulation the parent drug is rapidly eliminated and completely metabolized to hydrodolasetron by the ubiquitous enzyme, carbonyl reductase. Hydrodolasetron is widely distributed in the body and protein binding ranges 69—77% (approximately 50% to alpha-1-acid glycoprotein). Further metabolism of hydrodolasetron occurs primarily via cytochrome P450 2D6 to a hydroxylated metabolite. CYP3A and flavin monooxygenase are responsible for the N-oxidation of hydrodolasetron. Hydrodolasetron elimination is by multiple routes. Two thirds of the administered dose is recovered in the urine and one third in the feces. The elimination half-life of dolasetron and hydrodolasetron is < 10 minutes and 8.1 hours, respectively.
Affected cytochrome P450 isoenzymes: CYP2D6, CYP3A
Oral Route
Following oral administration, dolasetron is well absorbed. Peak plasma hydrodolasetron concentrations occur approximately 1 hour after dosing. The apparent absolute bioavailability of oral dolasetron, determined by the major active metabolite hydrodolasetron, is approximately 75%. Food does not affect the oral bioavailability of dolasetron. |
