Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI4TMRHXY)
Drug Name			Carbamazepine		Drug Info		Rifabutin		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Anticonvulsants/Antimanic Agents				Antibiotics
Structure

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

Drug Name		Carbamazepine				Rifabutin
Mechanism		CYP450 3A4 substrate				CYP450 3A4 inducer
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 3A4				× Structure Sequence MALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFDMECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIAEDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSMDVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVFPREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSIIFIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVNETLRLFPIAMRLERVCKKDVEINGMFIPKGVVVMIPSYALHRDPKYWTEPEKFLPERFSKKNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGGLLQPEKPVVLKVESRDGTVSGA
		Gene Name		CYP3A4
		Uniprot ID		CP3A4_HUMAN
		KEGG Pathway		hsa:1576
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:20702771, PubMed:19965576, PubMed:21490593, PubMed:21576599). 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). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:2732228, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:21576599, PubMed:21490593). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:14559847, PubMed:12865317). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:2732228, PubMed:15373842, PubMed:15764715, PubMed:22773874). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:2732228, PubMed:15373842, PubMed:15764715). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981). Click to Show/Hide
Mechanism Description		Increased metabolism of Carbamazepine caused by Rifabutin mediated induction of CYP450 enzyme

Recommended Action
Management		Pharmacologic effects and serum concentrations of carbamazepine should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the carbamazepine dosage adjusted as necessary.

References
1	Benetello P, Furlanut M "Primidone-carbamazepine interaction: clinical consequences." Int J Clin Pharmacol Res 7 (1987): 165-8. [PMID: 3583497]
2	Eichelbaum M, Kothe KW, Hoffmann F, von Unruh GE "Kinetics and metabolism of carbamazepine during combined antiepileptic drug therapy." Clin Pharmacol Ther 26 (1979): 366-71. [PMID: 466929]
3	Liu H, Delgado MR "Interactions of phenobarbital and phenytoin with carbamazepine and its metabolites' concentrations, concentration ratios, and level dose ratios in epileptic children." Epilepsia 36 (1995): 249-54. [PMID: 7614908]
4	Product Information. Tegretol (carbamazepine). Novartis Pharmaceuticals, East Hanover, NJ.
5	Ramsay RE, McManus DQ, Guterman A, et al "Carbamazepine metabolism in humans: effect of concurrent anticonvulsant therapy." Ther Drug Monit 12 (1990): 235-41. [PMID: 2112276]
6	Spina E, Martines C, Fazio A, Trio R, Pisani F, Tomson T "Effect of phenobarbital on the pharmacokinetics of carbamazepine-10, 11-epoxide, an active metabolite of carbamazepine." Ther Drug Monit 13 (1991): 109-12. [PMID: 2053116]
7	Tomson T, Spina E, Wedlund JE "Minor additive inducing effects of phenobarbital on carbamazepine clearance in patients on combined carbamazepine-phenytoin therapy." Ther Drug Monit 9 (1987): 117-9. [PMID: 3576657]
8	Zielinski JJ, Haidukewych D "Dual effects of carbamazepine-phenytoin interaction." Ther Drug Monit 9 (1987): 21-3. [PMID: 3576659]