Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIBFJAG6V)
Drug Name			Trimethoprim		Drug Info		Repaglinide		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antiinfective Agents				Antidiabetic Agents
Structure

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

Drug Name		Trimethoprim				Repaglinide
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 Repaglinide caused by Trimethoprim mediated inhibition of CYP450 enzyme

Recommended Action
Management		Because the antidiabetic effect of repaglinide is dose- and concentration-dependent, close monitoring for the development of hypoglycemia is recommended during coadministration with a CYP450 2C8 inhibitor. 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 repaglinide 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 repaglinide dosage adjusted as necessary.

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	Hatorp V "Clinical pharmacokinetics and pharmacodynamics of repaglinide." Clin Pharmacokinet 41 (2002): 471-83. [PMID: 12083976]
3	Niemi M, Kajosaari LI, Neuvonen M, Backman JT, Neuvonen PJ "The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects." Br J Clin Pharmacol 57 (2004): 441-7. [PMID: 15025742]
4	Skerjanec A, Wang J, Maren K, Rojkjaer L "Investigation of the pharmacokinetic interactions of deferasirox, a once-daily oral iron chelator, with midazolam, rifampin, and repaglinide in healthy volunteers." J Clin Pharmacol 50 (2010): 205-13. [PMID: 19940232]
5	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]