Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIBIRY236)
  Drug Name Irinotecan Drug Info Gemfibrozil Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antineoplastics Antihyperammonia Agents
  Structure

 Mechanism of Irinotecan-Gemfibrozil Interaction (Severity Level: Major)
     UGT inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Irinotecan Gemfibrozil
      Mechanism UGT1A1 substrate UGT1A1 inhibitor
      Key Mechanism Factor 1
Factor Name UDP-glucuronosyltransferase 1A1
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Structure Sequence
MAVESQGGRPLVLGLLLCVLGPVVSHAGKILLIPVDGSHWLSMLGAIQQLQQRGHEIVVLAPDASLYIRDGAFYTLKTYPVPFQREDVKESFVSLGHNVFENDSFLQRVIKTYKKIKKDSAMLLSGCSHLLHNKELMASLAESSFDVMLTDPFLPCSPIVAQYLSLPTVFFLHALPCSLEFEATQCPNPFSYVPRPLSSHSDHMTFLQRVKNMLIAFSQNFLCDVVYSPYATLASEFLQREVTVQDLLSSASVWLFRSDFVKDYPRPIMPNMVFVGGINCLHQNPLSQEFEAYINASGEHGIVVFSLGSMVSEIPEKKAMAIADALGKIPQTVLWRYTGTRPSNLANNTILVKWLPQNDLLGHPMTRAFITHAGSHGVYESICNGVPMVMMPLFGDQMDNAKRMETKGAGVTLNVLEMTSEDLENALKAVINDKSYKENIMRLSSLHKDRPVEPLDLAVFWVEFVMRHKGAPHLRPAAHDLTWYQYHSLDVIGFLLAVVLTVAFITFKCCAYGYRKCLGKKGRVKKAHKSKTH
Gene Name UGT1A1
Uniprot ID UD11_HUMAN
KEGG Pathway hsa:54658
Protein Family UDP-glycosyltransferase family
Protein Function
[Isoform 1]: UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004206, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:15472229, PubMed:18719240, PubMed:23288867). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (PubMed:17187418, PubMed:18004206, PubMed:19830808). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558).
    Click to Show/Hide
      Mechanism Description
  • Decreased metabolism of Irinotecan caused by Gemfibrozil mediated inhibition of UGT

Recommended Action
      Management Concomitant use of irinotecan with strong inhibitors of CYP450 3A4 and/or UGT1A1 should generally be avoided. If coadministration is required, patients should be monitored for toxicities such as diarrhea, myelosuppression, thromboembolism, and interstitial lung disease, and the irinotecan dosage adjusted accordingly or treatment discontinued as necessary.

References
1 Cerner Multum, Inc. "Australian Product Information.".
2 Cerner Multum, Inc. "UK Summary of Product Characteristics.".
3 Product Information. Camptosar (irinotecan). Pharmacia and Upjohn, Kalamazoo, MI.
4 Product Information. Onivyde (irinotecan liposomal). Merrimack Pharmaceuticals, Cambridge, MA.