Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI9WAFBHM)
Drug Name			Pioglitazone		Drug Info		Gemfibrozil		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antidiabetic Agents				Antihyperammonia Agents
Structure

Mechanism of Pioglitazone-Gemfibrozil Interaction (Severity Level: Major)
CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph

Drug Name		Pioglitazone				Gemfibrozil
Mechanism		CYP450 2C8 substrate				CYP450 2C8 inhibitor
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 2C8				× 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 Pioglitazone caused by Gemfibrozil mediated inhibition of CYP450 enzyme

Recommended Action
Management		Given the potential for dose-related adverse events, a lower dosage of pioglitazone may be necessary when used with gemfibrozil. The labeling recommends a maximum dosage of 15 mg daily when used with gemfibrozil or other potent CYP450 2C8 inhibitors. Close monitoring for the development of hypoglycemia and other adverse effects is recommended, such as fluid retention weight gain new or worsening heart failure pulmonary, peripheral, and macular edema bone fractures anemia and liver enzyme elevations. Patients should regularly monitor their blood sugar and learn how to recognize and treat hypoglycemia, which may include symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, and palpitation. Likewise, patients should be observed for potential loss of glycemic control following discontinuation of gemfibrozil, and the pioglitazone dosage adjusted as necessary.

References
1	Aquilante CL, Kosmiski LA, Bourne DW, et al. "Impact of the CYP2C8 *3 polymorphism on the drug-drug interaction between gemfibrozil and pioglitazone." Br J Clin Pharmacol 75 (2013): 217-26. [PMID: 22625877]
2	Daily EB, Aquilante CL "Cytochrome P450 2C8 pharmacogenetics: a review of clinical studies." Pharmacogenomics 10 (2009): 1489-510. [PMID: 19761371]
3	Deng LJ, Wang F, Li HD "Effect of gemfibrozil on the pharmacokinetics of pioglitazone." Eur J Clin Pharmacol 61 (2005): 831-6. [PMID: 16283275]
4	Jaakkola T, Backman JT, Neuvonen M, Neuvonen PJ "Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone." Clin Pharmacol Ther 77 (2005): 404-14. [PMID: 15900286]
5	Ogilvie BW, Zhang D, Li W, et al. "Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions." Drug Metab Dispos 34 (2006): 191-7. [PMID: 16299161]
6	Product Information. Actos (pioglitazone) Takeda Pharmaceuticals America, Lincolnshire, IL.
7	Scheen AJ "Pharmacokinetic interactions with thiazolidinediones." Clin Pharmacokinet 46 (2007): 1-12. [PMID: 17201456]
8	Totah RA, Rettie AE "Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance." Clin Pharmacol Ther 77 (2005): 341-52. [PMID: 15900280]