Clinical Pharmacokinetics of Ondansetron. A Review

Abstract

5-HT3 receptors are ubiquitous in the enteric, sympathetic, parasympathetic and sensory nervous systems and in the central nervous system (CNS) (Kilpatrick et al 1990). In man 5-HT3 receptors are mainly situated on enterochromaffin cells in the gastrointestinal mucosa, which are innervated by vagal afferents (Reynolds et al 1989), and the area postrema of the brain stem, which forms the chemoreceptor trigger zone. Ondansetron is a selective antagonist at 5-HT3 receptors. It is 100 times more potent than metoclopramide at this site (Tyers 1992). It shows limited binding to other receptors and has a wide therapeutic window. Ondansetron is a useful antiemetic which probably has both central and peripheral actions in patients undergoing radiotherapy, cytotoxic chemotherapy or general anaesthesia (Naylor & Rudd 1992). This paper reviews the pharmacokinetics of ondansetron in health and disease to provide information for clinicians; it might alter prescribing and alert them to possible drug interactions.

Gender differences in ondansetron pharmacokinetics in rats

“…Although the hepatic first-pass effect of ondansetron in humans does not seem to have been published, the effect was 'indirectly' estimated by dividing the hepatic clearance of the drug by the hepatic blood flow rate [26]. The effect was estimated based on the hepatic blood flow rate of 1450 ml/70 kg/min and the hematocrit of 0.45 in humans [22], and the intravenous ondansetron clearance of 702 ml/ min and 95% of the ondansetron dose was cleared in the liver in humans [27]. The hepatic first-pass effect of ondansetron thus estimated was 85.2%.…”

Prophylaxis of postoperative nausea and vomiting: controversies in the use of serotonin 5-hydroxytryptamine subtype 3 receptor antagonists

“…The reported plasma terminal half-lives (t 1/2 ) of each of the 5-HT 3 receptor antagonists vary considerably between studies (Table 3) [43][44][45][46][47][48][49][50][51][52][53][54][55][56]; however, they generally are less than 8 hours. The t 1/2 for ondansetron is highly dependent on the CYP2D6 metabolism phenotype.…”

“…Palonosetron, with a half-life of 40 hours, recently has been approved in the United States for use in chemotherapy-induced nausea and vomiting (CINV) [42] but is not yet available for prophylaxis or treatment of PONV. The distinguishing pharmacologic characteristics of these agents, such as differences in receptor selectivity and affinity, drug metabolism, and effects on cardiac ion channels (Table 3) [43][44][45][46][47][48][49][50][51][52][53][54][55][56] are presented below. The general pharmacologic properties of dolasetron, granisetron, ondansetron, and tropisetron have been reviewed elsewhere [3,57,58].…”

“…The 5-HT 3 receptor antagonists are extensively metabolized by hepatic enzymes of the CYP450 family, with CYP2D6 being the predominant enzyme responsible for metabolism of dolasetron [46] and tropisetron (Table 3) [43][44][45][46][47][48][49][50][51][52][53][54][55][56]. Although CYP2D6 also is involved in the metabolism of ondansetron [46,48], it appears to be only one of several enzymes that plays a role [46,47].…”

“…[43][44][45][46][47][48][49][50][51][52][53][54][55][56]. Although the clinical relevance of these interactions is not clear, they may increase the potential for drug interactions betweenMethods to Reduce Baseline PONV Risk…”