The polymorphic cytochrome P-4502D6 is involved in the metabolism of both 5-hydroxytryptamine antagonists, tropisetron and ondansetron.
Tropisetron and ondansetron, which are potent and selective 5-hydroxytryptamine (5-HT3) receptor antagonists, were both metabolized by human liver microsomes to several metabolites. These metabolites include the major metabolites found in humans, which are the 5-, 6-, and 7-hydroxy tropisetron and the 7- and 8-hydroxy ondansetron. The cytochrome P-450 (CYP) 2D6 inhibitor quinidine (1 microM) reduced the hydroxylation of tropisetron (67%) and ondansetron (18%). Confirmation of CYP2D6 involvement in the hydroxylation of tropisetron and ondansetron was obtained by the formation of these metabolites in recombinant V79 cells expressing human CYP2D6. The CYP3A substrate/inhibitor, cyclosporine A (CsA) had little effect on tropisetron hydroxylation (< 10%), whereas CsA and triacetyloleandomycin reduced ondansetron 7- and 8-hydroxylation up to 27%. Substrates for CYP1A (phenacetin and acetanilide), CYP2C (mephenytoin), and CYP2E (chlorzoxazone) had negligible inhibitory effects on the hydroxylation of either tropisetron or ondansetron. For the CYP2D6-dependent O-demethylation of dextromethorphan, tropisetron and ondansetron were competitive inhibitors with Ki values of 14 and 29 microM, respectively. The CYP3A specific metabolism of CsA was also competitively inhibited by tropisetron (Ki = 2.1 mM) and ondansetron (Ki = 31 microM). Other metabolites, which are only minor in vivo were also inhibited by CsA, 47-60% for tropisetron metabolism and 43% for ondansetron metabolism. To summarize, this study has identified the involvement of CYP2D6 in the formation of the hydroxylated metabolites of tropisetron and ondansetron and in addition of CYP3A in ondansetron hydroxylation. Because these are the major pathways in vivo, coadministration of drugs competing for CYP2D6 and possibly CYP3A4 could influence the human kinetics of tropisetron and ondansetron.
Sandoz Pharma Ltd., Basel, Switzerland.
V
V
Fischer
A E
AE
Vickers
F
F
Heitz
S
S
Mahadevan
J P
JP
Baldeck
P
P
Minery
R
R
Tynes
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007211:Indoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017294:Ondansetron / Q000493:pharmacokinetics* / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000493:pharmacokinetics*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D000077526:Tropisetron
D065607:Cytochrome P-450 Enzyme Inhibitors; D007211:Indoles; D012702:Serotonin Antagonists; D017294:Ondansetron; D000077526:Tropisetron; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6