PT - JOURNAL ARTICLE AU - Virginie Charasson AU - Marie-Christine Haaz AU - Jacques Robert TI - Determination of Drug Interactions Occurring with the Metabolic Pathways of Irinotecan AID - 10.1124/dmd.30.6.731 DP - 2002 Jun 01 TA - Drug Metabolism and Disposition PG - 731--733 VI - 30 IP - 6 4099 - http://dmd.aspetjournals.org/content/30/6/731.short 4100 - http://dmd.aspetjournals.org/content/30/6/731.full SO - Drug Metab Dispos2002 Jun 01; 30 AB - Irinotecan or CPT-11 [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] is a derivative of camptothecine used in the treatment of advanced colorectal cancer. It requires activation to SN-38 (7-ethyl-10-hydroxycamptothecine) by carboxylesterase. Irinotecan and SN-38 are detoxified through two major metabolic pathways: the first one leads to oxidative degradation compounds, APC [7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecine] and NPC [7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine], and involves cytochrome P450 (3A4 isoform); the second one leads to SN-38 glucuronide (SN-38G) and involves UDP-glucuronosyltransferase (UGT). Using human hepatic microsomes, we studied the interactions of 15 drugs of common use in colorectal cancer patients on these metabolic pathways. Only nifedipine had a significant effect on SN-38 formation, decreasing carboxylesterase activity by 50% at 100 μM and 35% at 10 μM. Three drugs had a significant effect on SN-38G formation: clonazepam increased UGT activity by 50% at 100 μM and 30% at 10 μM, and nifedipine and vinorelbine inhibited the activity by 65 and 55% at 100 μM, respectively, with no effect at 10 μM. Five drugs exerted a significant inhibition on SN-38 formation at 100 μM: clonazepam (70%), methylprednisolone (50%), nifedipine (80%), omeprazole (85%), and vinorelbine (100%). Only omeprazole and vinorelbine still exerted a significant inhibition at 10 μM (30 and 90%, respectively), whereas only vinorelbine had a significant effect at 2 and 0.5 μM (70 and 40%, respectively). In conclusion, potential clinical interactions with the metabolism of irinotecan are likely to be important for vinorelbine, which strongly inhibits irinotecan catabolism by CYP3A4 at clinically relevant concentrations, but not for the other drugs, which exert an effect at concentrations not achievable in patients. The American Society for Pharmacology and Experimental Therapeutics