Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIXHDI9ET)
Drug Name			Carbamazepine		Drug Info		Dextropropoxyphene		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Anticonvulsants/Antimanic Agents				Analgesics
Structure

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

Drug Name		Carbamazepine				Dextropropoxyphene
Mechanism		CYP450 substrate				CYP450 inhibitor
Key Mechanism Factor 1
		Factor Name		Cytochrome P450				Structure Sequence
		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		Decreased metabolism of Carbamazepine caused by Dextropropoxyphene mediated inhibition of CYP450 enzyme

Recommended Action
Management		Given the availability of alternative analgesics, the use of propoxyphene in combination with carbamazepine should generally be avoided. A dose adjustment of carbamazepine may be required if concomitant use is necessary, and serum carbamazepine levels should be closely monitored. Patients should be advised to seek medical attention if they develop potential signs and symptoms of carbamazepine toxicity such as headache, nausea, dizziness, slurred speech, nystagmus, visual disturbances, tremors, and ataxia.

References
1	Allen S "Cerebellar dysfunction following dextropropoxyphene-induced carbamazepine toxicity." Postgrad Med J 70 (1994): 764. [PMID: 7831181]
2	Kubacka RT, Ferrante JA "Carbamazepine-propoxyphene interaction." Clin Pharm 2 (1983): 104. [PMID: 6883938]
3	Spina E, Pisani F, Perucca E "Clinically significant pharmacokinetic drug interactions with carbamazepine - an update." Clin Pharmacokinet 31 (1996): 198-214. [PMID: 8877250]