In vitro characterization of cytochrome P450 catalysed metabolism of the antiemetic tropisetron

Firkusny, Lucie; Kroemer, Heyo K.; Eichelbaum, Michel

doi:10.1016/0006-2952(95)00021-q

Cited by 32 publications

(11 citation statements)

References 20 publications

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“…Antiemetics. The major route of elimination of the 5-hydroxytryptamine 3 antagonist, tropisetron, in EMs is via metabolism to 6-hydroxyatomoxetine and 5-hydroxytropisetron and their conjugates (ϳ50 -60% of the dose excreted) whereas PMs excrete only trace amounts (Fischer et al, 1994;Firkusny et al, 1995;Sanwald et al, 1996). Early work demonstrated 5-to 7-fold higher AUCs in PMs (de Bruijn, 1992).…”

Section: Antipsychoticsmentioning

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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Section: Antipsychoticsmentioning

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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“…To predict pharmacokinetic interactions, a major enzyme responsible for the concomitant metabolism of the drugs being used should be recognized. However, the major enzymes responsible for the metabolism of granisetron remain unknown, although those for other antiemetic drugs, such as ondansetron, dolasetron and tropisetron, have been already reported [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

CYP1A1 Is a Major Enzyme Responsible for the Metabolism of Granisetron in Human Liver Microsomes

Nakamura¹,

Ariyoshi²,

Okada

et al. 2005

CDM

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Granisetron, a potent 5-HT3 receptor antagonist, has been reported to be mainly metabolized to 7-hydroxygranisetron and a lesser extent to 9'-desmethylgranisetron in humans. A previous study indicated that cytochrome P450 (CYP)3A4 is a major catalyst of 9'-demethylation, although the major CYP isoform(s) responsible for 7-hydroxylation are unknown. To clarify granisetron 7-hydroxylase, the in vitro metabolism of granisetron using expressed human CYPs and human liver microsomes was investigated. 7-Hydroxygranisetron was produced almost exclusively by CYP1A1, while, apparently, 9'-desmethylgranisetron was preferentially produced by CYP3A4. Marked inter-individual differences in the ratio of the formation of 7-hydroxygranisetron and 9'-desmethylgranisetron in human liver microsomes was observed. Granisetron 7-hydroxylase activity was strongly correlated with benzo[a]pyrene 3-hydroxylase activity (p<0.0001), but not with testosterone 6beta-hydroxylase activity in human liver microsomes. Furthermore, an anti-human CYP1A1 antibody completely inhibited 7-hydroxylation in human liver microsomes, however, the reaction was not inhibited at all by an anti-CYP3A4 antibody. On the other hand, granisetron 9'-demethylase activity correlated significantly not only with testosterone 6beta-hydroxylase activity (p<0.0001) but also with benzo[a]pyrene 3-hydroxylase activity (p<0.01). Consistent with this, both the anti-CYP1A1 and anti-human CYP3A4 antibodies inhibited the 9'-demethylase activity. These data indicate that CYP1A1 is a major enzyme responsible for the metabolism of granisetron via a main 7-hydroxylation pathway and an alternative 9'-demethylation route. This is the first report demonstrating the substantial contribution of CYP1A1 to the metabolism of a drug, although its role in the metabolism of environmental compounds is well established.

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“…In contrast, granisetron is metabolized by members of the CYP3A family only and has not been found to induce or inhibit this enzyme [56, 62]. Tropisetron metabolism is almost exclusively CYP2D6 dependent [55]. As shown in table 3, granisetron is the only 5-HT 3 -receptor antagonist not metabolized in part by CYP2D6.…”

Section: Drug-drug Interactionsmentioning

confidence: 99%

5-HT<sub>3</sub>-Receptor Antagonists in the Management of Nausea and Vomiting in Cancer and Cancer Treatment

Aapro¹

2005

Oncology

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The 5-HT₃-receptor antagonists, considered as ‘gold standard’ therapy for cancer patients, are generally perceived to have similar efficacy and safety profiles, andmost antiemetic guidelines do not distinguish between agents. However, important pharmacological differences exist between agents, which may translate into potential benefits for some patients. In particular, 5-HT₃-receptor antagonists vary in the nature of their receptor antagonism and plasma half-lives, possibly leading to differences in duration of action. Agents with a longer duration of action provide antiemetic protection throughout the acute emetic period (24 h) with a single daily dose, whereas shorter-acting agents, e.g. ondansetron, may require multiple dosing for full efficacy. Differences also exist between agents in their hepatic metabolism and cardiovascular safety, which may present particular problems for elderly patients who often receive additional medications for comorbid conditions, increasing the risk of drug-drug interaction. Recent antiemetic guidelines from the National Comprehensive Cancer Network recommend preferential use of palonosetron for moderately emetogenic chemotherapy; however, this agent is newly approved and key clinical questions remain unanswered by clinical trial data. Selection of an appropriate 5-HT₃-receptor antagonist should be based on proven efficacy and safety, as well as on the individual characteristics of the patient.

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In vitro characterization of cytochrome P450 catalysed metabolism of the antiemetic tropisetron

Cited by 32 publications

References 20 publications

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

CYP1A1 Is a Major Enzyme Responsible for the Metabolism of Granisetron in Human Liver Microsomes

5-HT<sub>3</sub>-Receptor Antagonists in the Management of Nausea and Vomiting in Cancer and Cancer Treatment

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