Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDI5X7VFD2)
  Drug Name Repaglinide Drug Info Gemfibrozil Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antidiabetic Agents Antihyperammonia Agents
  Structure

 Mechanism of Repaglinide-Gemfibrozil Interaction (Severity Level: Major)
     Transporter inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Repaglinide Gemfibrozil
      Mechanism 1 OATP1B1 substrate OATP1B1 inhibitor
      Key Mechanism Factor 1
Factor Name Liver organic anion transporter 1
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Structure Sequence
MDQNQHLNKTAEAQPSENKKTRYCNGLKMFLAALSLSFIAKTLGAIIMKSSIIHIERRFEISSSLVGFIDGSFEIGNLLVIVFVSYFGSKLHRPKLIGIGCFIMGIGGVLTALPHFFMGYYRYSKETNINSSENSTSTLSTCLINQILSLNRASPEIVGKGCLKESGSYMWIYVFMGNMLRGIGETPIVPLGLSYIDDFAKEGHSSLYLGILNAIAMIGPIIGFTLGSLFSKMYVDIGYVDLSTIRITPTDSRWVGAWWLNFLVSGLFSIISSIPFFFLPQTPNKPQKERKASLSLHVLETNDEKDQTANLTNQGKNITKNVTGFFQSFKSILTNPLYVMFVLLTLLQVSSYIGAFTYVFKYVEQQYGQPSSKANILLGVITIPIFASGMFLGGYIIKKFKLNTVGIAKFSCFTAVMSLSFYLLYFFILCENKSVAGLTMTYDGNNPVTSHRDVPLSYCNSDCNCDESQWEPVCGNNGITYISPCLAGCKSSSGNKKPIVFYNCSCLEVTGLQNRNYSAHLGECPRDDACTRKFYFFVAIQVLNLFFSALGGTSHVMLIVKIVQPELKSLALGFHSMVIRALGGILAPIYFGALIDTTCIKWSTNNCGTRGSCRTYNSTSFSRVYLGLSSMLRVSSLVLYIILIYAMKKKYQEKDINASENGSVMDEANLESLNKNKHFVPSAGADSETHC
Gene Name OATP1B1
Uniprot ID SO1B1_HUMAN
KEGG Pathway hsa:10599
Protein Family Organo anion transporter (TC 2.A.60) family
Protein Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver.
    Click to Show/Hide
      Mechanism Description
  • Decreased clearance of Repaglinide due to the transporter inhibition by Gemfibrozil 
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Repaglinide Gemfibrozil
      Mechanism 2 CYP450 2C8 substrate CYP450 2C8 inhibitor
      Key Mechanism Factor 2
Factor Name Cytochrome P450 2C8
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Structure Sequence
MEPFVVLVLCLSFMLLFSLWRQSCRRRKLPPGPTPLPIIGNMLQIDVKDICKSFTNFSKVYGPVFTVYFGMNPIVVFHGYEAVKEALIDNGEEFSGRGNSPISQRITKGLGIISSNGKRWKEIRRFSLTTLRNFGMGKRSIEDRVQEEAHCLVEELRKTKASPCDPTFILGCAPCNVICSVVFQKRFDYKDQNFLTLMKRFNENFRILNSPWIQVCNNFPLLIDCFPGTHNKVLKNVALTRSYIREKVKEHQASLDVNNPRDFIDCFLIKMEQEKDNQKSEFNIENLVGTVADLFVAGTETTSTTLRYGLLLLLKHPEVTAKVQEEIDHVIGRHRSPCMQDRSHMPYTDAVVHEIQRYSDLVPTGVPHAVTTDTKFRNYLIPKGTTIMALLTSVLHDDKEFPNPNIFDPGHFLDKNGNFKKSDYFMPFSAGKRICAGEGLARMELFLFLTTILQNFNLKSVDDLKNLNTTAVTKGIVSLPPSYQICFIPV
Gene Name CYP2C8
Uniprot ID CP2C8_HUMAN
KEGG Pathway hsa:1558
Protein Family Cytochrome P450 family
Protein Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:7574697, PubMed:15766564, PubMed:19965576). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316).
    Click to Show/Hide
      Mechanism Description
  • Decreased metabolism of Repaglinide caused by Gemfibrozil mediated inhibition of CYP450 enzyme

Recommended Action
      Management Concomitant use of repaglinide and gemfibrozil is considered contraindicated. alternatives to gemfibrozil in patients taking repaglinide include bezafibrate and fenofibrate, which have been shown not to interact pharmacokinetically with repaglinide. In patients treated with gemfibrozil with or without itraconazole, nateglinide may be an appropriate substitution for repaglinide.

References
1 Bidstrup TB, Bjornsdottir I, Sidelmann UG, Thomsen MS, Hansen KT "CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide." Br J Clin Pharmacol 56 (2003): 305-14. [PMID: 12919179]
2 Kajosaari LI, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ "Lack of effect of bezafibrate and fenofibrate on the pharmacokinetics and pharmacodynamics of repaglinide." Br J Clin Pharmacol 58 (2004): 390-6. [PMID: 15373931]
3 Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT "Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin." Basic Clin Pharmacol Toxicol 97 (2005): 249-56. [PMID: 16176562]
4 Niemi M, Backman JT, Juntti-Patinen L, Neuvonen M, Neuvonen PJ "Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide." Br J Clin Pharmacol 60 (2005): 208-17. [PMID: 16042675]
5 Niemi M, Backman JT, Kajosaari LI, et al. "Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics." Clin Pharmacol Ther 77 (2005): 468-78. [PMID: 15961978]
6 Product Information. Prandin (repaglinide). Novo Nordisk Pharmaceuticals Inc, Princeton, NJ.
7 Niemi M, Backman JT, Neuvonen M, Neuvonen PJ "Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide." Diabetologia 46 (2003): 347-51. [PMID: 12687332]