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Serotonin-norepinephrine reuptake inhibitor antidepressants: Pharmacokinetics

Drug	Bioavailability (percent)	Time to peak plasma concentration (hours)	Primary metabolism*	Active metabolite(s)	Effect(s) on drug metabolism*	Elimination half-life (hours)	Clearance
Desvenlafaxine	80 Unaffected by food	7.5 to 9	UGT glucuronidation	No	None	9 to 11 Prolonged in renal or hepatic impairment	Renal and hepatic; 45% excreted unchanged Dose adjustment needed in renal or hepatic impairment
Duloxetine	50 Wide interindividual variation (30 to 80); minimally affected by food	6 (unfed) 10 (fed)	CYP1A2, CYP2D6	No	Inhibits CYP2D6	10 to 12 Prolonged in hepatic impairment	Hepatic and renal; avoid in hepatic insufficiency (any degree), liver disease, or substantial alcohol use Dose adjustment needed in renal impairment
Levomilnacipran ER	>90 Unaffected by food	6 to 8 Avoid concurrent administration with alcohol which can accelerate release of levomilnacipran from the extended-release preparation	Primarily CYP3A4	No	None	12 Prolonged in moderate to severe renal impairment	Renal and hepatic; 50 to 60% excreted unchanged Dose adjustment needed renal impairment
Milnacipran	85 to 90 Unaffected by food	2 to 4	Glucuronidation	No	None	8 to 10 Prolonged in moderate to severe renal impairment and severe hepatic impairment	Renal and hepatic; 50 to 60% excreted unchanged Dose adjustment needed in renal impairment
Venlafaxine
Immediate release	13^¶ Unaffected by food	1 to 2	CYP2D6, CYP3A4	Yes (desvenlafaxine also known as O-dexmethylvenlafaxine or ODV)	None	5 (parent) 11 (active metabolite) Prolonged in renal or hepatic impairment	Renal and hepatic; ~34% excreted as active desvenlafaxine (ODV) or unchanged Dose adjustment needed in renal or hepatic impairment
Extended release	45^¶ Unaffected by food	5.5	CYP2D6, CYP3A4		None

CYP: cytochrome P450; UGT: uridine diphosphate glucuronosyltransferase.
* The classification of effects on drug metabolism are based upon US Food and Drug Administration (FDA) guidance.^[1,2] Other sources may use a different classification system resulting in some agents being classified differently. Weak inhibitor effects are not listed. Clinically significant interactions can occasionally occur due to weak inhibitors, particularly if the target drug has a narrow therapeutic margin. Refer to the Lexicomp drug interactions program for a full review of potential interactions.
¶ Oral bioavailability is increased by two- to threefold in mild to moderate hepatic impairment.

Data from:

Spina E, Trifirò G, Caraci F. Clinically significant drug interactions with newer antidepressants. CNS Drugs 2012; 26:39.
Yang LP, Plosker GL. Desvenlafaxine extended release. CNS Drugs 2008; 22:1061.
Thase ME. Venlafaxine and desvenlafaxine. In: The American Psychiatric Association Publishing Textbook of Psychopharmacology, 5th ed, Schatzberg AF, Nemeroff CB (Eds), American Psychiatric Association Publishing, Inc., Arlington 2017. p.515.
Norris S, Blier P. Duloxetine, milnacipran, and levomilnacipran. In: The American Psychiatric Association Publishing Textbook of Psychopharmacology, 5th ed, Schatzberg AF, Nemeroff CB (Eds), American Psychiatric Association Publishing, Arlington 2017. p.529.
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References:

US Food and Drug Administration. Clinical drug interaction studies — Cytochrome P450 enzyme- and transporter-mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions (Accessed on June 5, 2020).
US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website.

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