Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIV4RZONJ)
Drug Name			Paroxetine		Drug Info		Nebivolol		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antidepressants				Antihypertensive Agents
Structure

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

Drug Name		Paroxetine				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 Paroxetine mediated inhibition of CYP450 enzyme

Recommended Action
Management		During concomitant therapy with SSRIs, a lower initial dosage and more cautious titration of the beta-blocker may be appropriate. Cardiac function should be closely monitored and the beta-blocker dosage adjusted accordingly, particularly following initiation, discontinuation or change of dosage of SSRI in patients who are stabilized on their beta-blocker regimen. Due to the long half-life of fluoxetine and its active metabolite, norfluoxetine, the risk of an interaction may exist for an extended period (up to several weeks) after discontinuation of fluoxetine. To avoid the interaction, use of beta-blockers that are primarily eliminated by the kidney such as atenolol, acebutolol, betaxolol, carteolol, and nadolol may be considered.

References
1	Amchin J, Ereshefsky L, Zarycranski W, Taylor K, Albano D, Klockowski PM "Effect of venlafaxine versus fluoxetine on metabolism of dextromethorphan, a CYP2D6 probe." J Clin Pharmacol 41 (2001): 443-51. [PMID: 11304901]
2	Brosen K, Skjelbo E, Rasmussen BB, Poulsen HE, Loft S "Fluvoxamine is a potent inhibitor of cytochrome P4501A2." Biochem Pharmacol 45 (1993): 1211-4. [PMID: 8466541]
3	Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE "The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes." Br J Clin Pharmacol 34 (1992): 262-5. [PMID: 1389951]
4	Drake WM, Gordon GD "Heart block in a patient on propranolol and fluoxetine." Lancet 343 (1994): 425-6. [PMID: 7905586]
5	Schimmel J, Manini AF. Opioid Use Disorder and COVID-19: Biological Plausibility for Worsened Outcomes. Subst Use Misuse. 2020;55(11):1900-1901. [PMID: 32657207]
6	Gilman AG, Rall TW, Nies AS, Taylor P, eds. "Goodman and Gilman's the Pharmacological Basis of Therapeutics. 8th ed." New York, NY: Pergamon Press Inc. (1990):.
7	Hemeryck A, DeVriendt CA, Belpaire FM "Metoprolol-paroxetine interaction in human liver microsomes: Stereoselective aspects and prediction of the in vivo interaction." Drug Metab Disposition 29 (2001): 656-63. [PMID: 11302931]
8	Hemeryck A, Lefebvre RA, DeVriendt C, Belpaire FM "Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers." Clin Pharmacol Ther 67 (2000): 283-91. [PMID: 10741632]
9	Kashuba ADM, Nafziger AN, Kearns GL, Leeder JS, Gotschall R, Rocci ML, Kulawy RW, Beck DJ, Bertino JS "Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping." Clin Pharmacol Ther 64 (1998): 257-68. [PMID: 9757149]
10	Nemeroff CB, Devane CL, Pollock BG "Newer antidepressants and the cytochrome p450 system." Am J Psychiatry 153 (1996): 311-20. [PMID: 8610817]
11	Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM "Inhibition by fluoxetine of cytochrome P450 2D6 activity." Clin Pharmacol Ther 53 (1993): 401-9. [PMID: 8477556]
12	Perucca E, Gatti G, Spina E "Clinical pharmacokinetics of fluvoxamine." Clin Pharmacokinet 27 (1994): 175-90. [PMID: 7988100]
13	Product Information. Luvox (fluvoxamine). Solvay Pharmaceuticals Inc, Marietta, GA.
14	Richelson E "Pharmacokinetic interactions of antidepressants." J Clin Psychiatry 59 (1998): 22-6. [PMID: 9720479]
15	Riesenman C "Antidepressant drug interactions and the cytochrome p450 system: a critical appraisal." Pharmacotherapy 15 (1995): s84-99. [PMID: 8587855]
16	Walley T, Pirmohamed M, Proudlove C, Maxwell D "Interaction of metoprolol and fluoxetine." Lancet 341 (1993): 967-8. [PMID: 8096308]