Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIPK5MAWH)
Drug Name			Rifabutin		Drug Info		Pioglitazone		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antibiotics				Antidiabetic Agents
Structure

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

Drug Name		Rifabutin				Pioglitazone
Mechanism		CYP450 2C8 inducer				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		Increased metabolism of Pioglitazone caused by Rifabutin mediated induction of CYP450 enzyme

Recommended Action
Management		Because the antidiabetic effect of pioglitazone is dose- and concentration-dependent, patients treated concomitantly with a CYP450 2C8 inducer may require a higher dosage of pioglitazone. Close clinical monitoring of glycemic control is recommended following initiation or discontinuation of the CYP450 2C8 inducer, and the pioglitazone dosage adjusted as necessary.

References
1	Jaakkola T, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ "Effect of rifampicin on the pharmacokinetics of pioglitazone." Br J Clin Pharmacol 61 (2006): 70-8. [PMID: 16390353]
2	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]
3	Product Information. Actos (pioglitazone) Takeda Pharmaceuticals America, Lincolnshire, IL.
4	Scheen AJ "Pharmacokinetic interactions with thiazolidinediones." Clin Pharmacokinet 46 (2007): 1-12. [PMID: 17201456]
5	Totah RA, Rettie AE "Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics, and clinical relevance." Clin Pharmacol Ther 77 (2005): 341-52. [PMID: 15900280]