Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIL1NCPRX)
Drug Name			Trimethoprim		Drug Info		Pioglitazone		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antiinfective Agents				Antidiabetic Agents
Structure

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

Drug Name		Trimethoprim				Pioglitazone
Mechanism		CYP450 2C8 inhibitor				CYP450 2C8 substrate
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 Trimethoprim mediated inhibition of CYP450 enzyme

Recommended Action
Management		Given the potential for dose-related adverse events with pioglitazone, caution is advised during coadministration with 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. The dosage of pioglitazone may require adjustment if an interaction is suspected. Likewise, patients should be observed for potential loss of glycemic control following discontinuation of the CYP450 2C8 inhibitor, 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	Jaakkola T, Laitila J, Neuvonen PJ, Backman JT "Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors." Basic Clin Pharmacol Toxicol 99 (2006): 44-51. [PMID: 16867170]
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]
9	Wen X, Wang JS, Backman JT, Laitila J, Neuvonen PJ "Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively." Drug Metab Dispos 30 (2002): 631-635. [PMID: 12019187]