Determination of the human cytochrome P450 isoforms involved in the metabolism of zolmitriptan.
1. Zolmitriptan was extensively metabolized by freshly isolated human hepatocytes to a number of components including the three main metabolites observed in vivo (N-desmethyl-zolmitriptan, zolmitriptan N-oxide and the indole acetic acid derivative). In contrast, metabolism of zolmitriptan by human hepatic microsomes was extremely limited with only small amounts of the N-desmethyl and indole ethyl alcohol metabolites being produced. 2. Furafylline, a selective inhibitor of CYP1A2, almost completely abolished the hepatocellular metabolism of zolmitriptan and markedly inhibited formation of the N-desmethyl metabolite in microsomes. Chemical inhibitors, selective against other major human cytochrome P450 (CYP2C9, 2C19, 2D6 and 3A4), had no obvious effects. In addition, expressed human CYP1A2 was the only cytochrome P450 to form the N-desmethyl metabolite. 3. N-desmethyl-zolmitriptan was extensively metabolized by both human hepatocytes and microsomes. The indole acetic acid and ethyl alcohol derivatives were the major metabolites formed by hepatocytes, whereas only the indole ethyl alcohol derivative was produced by microsomes. Metabolism of N-desmethyl-zolmitriptan was not inhibited by cytochrome P450-selective chemical inhibitors nor was it observed following incubation with expressed human cytochrome P450. Clorgyline, a selective inhibitor of monoamine oxidase A (MAO-A), markedly inhibited the microsomal formation of the indole ethyl alcohol derivative. 4. Primary metabolism of zolmitriptan is dependent mainly on CYP1A2, whereas MAO-A is responsible for further metabolism of N-desmethyl-zolmitriptan, the active metabolite. Since the in vivo clearance of zolmitriptan is primarily dependent on metabolism, interactions with drugs that induce or inhibit CYP1A2 or MAO-A may be anticipated.
Wild
M J
MJ
Drug Kinetics Group, Safety of Medicines Department, Zeneca Pharmaceuticals, Macclesfield, UK. Martin.Wild@ALDERLEY.ZENECA.com
McKillop
D
D
Butters
C J
CJ
D002927:Cimetidine / Q000494:pharmacology; D003010:Clorgyline / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007527:Isoenzymes; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology; D010080:Oxazoles / Q000378:metabolism*; D023303:Oxazolidinones; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000378:metabolism*; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014363:Tryptamines
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010080:Oxazoles; D023303:Oxazolidinones; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; C050131:furafylline; D009853:Omeprazole; D003010:Clorgyline; D007654:Ketoconazole