Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI8N2MU7W)
Drug Name			Quinidine		Drug Info		Nebivolol		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Group I Antiarrhythmics				Antihypertensive Agents
Structure

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

Drug Name		Quinidine				Nebivolol
Mechanism		CYP450 2D6 inhibitor				CYP450 2D6 substrate
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 2D6				× Structure Sequence MGLEALVPLAVIVAIFLLLVDLMHRRQRWAARYPPGPLPLPGLGNLLHVDFQNTPYCFDQLRRRFGDVFSLQLAWTPVVVLNGLAAVREALVTHGEDTADRPPVPITQILGFGPRSQGVFLARYGPAWREQRRFSVSTLRNLGLGKKSLEQWVTEEAACLCAAFANHSGRPFRPNGLLDKAVSNVIASLTCGRRFEYDDPRFLRLLDLAQEGLKEESGFLREVLNAVPVLLHIPALAGKVLRFQKAFLTQLDELLTEHRMTWDPAQPPRDLTEAFLAEMEKAKGNPESSFNDENLRIVVADLFSAGMVTTSTTLAWGLLLMILHPDVQRRVQQEIDDVIGQVRRPEMGDQAHMPYTTAVIHEVQRFGDIVPLGVTHMTSRDIEVQGFRIPKGTTLITNLSSVLKDEAVWEKPFRFHPEHFLDAQGHFVKPEAFLPFSAGRRACLGEPLARMELFLFFTSLLQHFSFSVPTGQPRPSHHGVFAFLVSPSPYELCAVPR
		Gene Name		CYP2D6
		Uniprot ID		CP2D6_HUMAN
		KEGG Pathway		hsa:1565
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, 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) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants. Click to Show/Hide
Mechanism Description		Decreased metabolism of Nebivolol caused by Quinidine mediated inhibition of CYP450 enzyme

Recommended Action
Management		Patients should be monitored for orthostatic hypotension, cardiac arrhythmias, bradycardia, and heart failure, and beta-blocker dosage should be decreased if necessary.

References
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3	Edeki TI, He H, Wood AJ "Pharmacogenetic explanation for excessive B-blockade following timolol eye drops." JAMA 274 (1995): 1611-3. [PMID: 7474246]
4	Fenster P, Perrier D, Mayersohn M, Marcus FI "Kinetic evaluation of the propranolol-quinidine combination." Clin Pharmacol Ther 27 (1980): 450-3. [PMID: 7357801]
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6	Leemann T, Dayer P, Meyer UA "Single-dose quinidine treatment inhibits metoprolol oxidation in extensive metabolizers." Eur J Clin Pharmacol 29 (1986): 739-41. [PMID: 3709620]
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9	Ochs HR, Greenblatt DJ, Woo E, et al "Effect of propranolol on pharmacokinetics and acute electrocardiographic changes following intravenous quinidine in humans." Pharmacology 17 (1978): 301-6. [PMID: 733889]
10	Zhou HH, Anthony LB, Roden DM, Wood AJ "Quinidine reduces clearance of (+)-propranolol more than (-)-propranolol through marked reduction in 4-hydroxylation." Clin Pharmacol Ther 47 (1990): 686-93. [PMID: 2357863]
11	Zhou HH, Wood AJ "Differences in stereoselective disposition of propranolol do not explain sensitivity differences between white and Chinese subjects: correlation between the clearance of (-)- and (+)- propranolol." Clin Pharmacol Ther 47 (1990): 719-23. [PMID: 2357866]