Paroxetine Category: pharmacological
Aliases: Paxil, Seroxat
Pharmacological Mechanism Most potent SSRI at SERT + has weak anticholinergic + NE reuptake activity. Strong CYP2D6 inhibitor. Shortest t½ among SSRIs → most notorious discontinuation syndrome.
Half-Life (t½) PO: 20h
Dosing Guidelines PO: Typical 26.7 mg (Range: 10–60 mg)Target Organ Systems Interactions Tamoxifen (major): Blocks CYP2D6-mediated endoxifen formation — reduces efficacy. Choose non-inhibitor SSRI (venlafaxine, citalopram) in hot-flash management. [Zanger 2004]Metoprolol (major): CYP2D6 inhibition (TDI). Hemeryck 2000 (PMID:10741632) n=8 healthy male EMs, metoprolol 100 mg single ± paroxetine 20 mg/d × 6d: (R)-AUC 169→1340 ng·h/mL (7.93×), (S)-AUC 279→1418 (5.08×). Ki ≈ 0.2/4.08 = 0.049 µM (S-enant basis). Loss of cardioselectivity, bradycardia.Atomoxetine (warn): CYP2D6 inhibition. Jung 2020 (PMID:33245517) n=10 CYP2D6*wt/*wt, atomoxetine 20 mg single ± paroxetine 20 mg/d × 6d: AUC0-24 increased 2.3× (in *wt/*wt EMs; 1.7× in *wt/*10, 1.3× in *10/*10). Ki ≈ 0.2/1.3 = 0.15 µM. FDA label recommends dose reduction.Desipramine (major): CYP2D6 inhibition (TDI). Brøsen 1993 (PMID:8513845) n=9 EMs + 8 PMs, desipramine 100 mg single ± paroxetine 20 mg/d: 5-fold CL decrease in EMs (median CL 22→4.4 L/h). AUC ratio ~5×. Ki ≈ 0.2/4 = 0.05 µM. TCA narrow therapeutic index — dose reduction required. Corroborated by Laine 2004 (PMID:14730412): 4.8× AUC.Risperidone (warn): CYP2D6 inhibition (parent → 9-OH conversion). Spina 2001 (PMID:11360029) n=10 schizophrenia patients, risperidone 4-8 mg/d + paroxetine 20 mg/d × 4 wk: active-moiety (risperidone + 9-OH) +45% (P<0.05); EPS in 1/10. Ki ≈ 0.2/0.45 = 0.44 µM (active-moiety basis underestimates parent shift).Aripiprazole (warn): CYP2D6 inhibition. Azuma 2012 (PMID:21739267) n=14 EMs + 14 IMs Japanese, aripiprazole 3 mg single + paroxetine 20 mg/d × 6-7d: CL/F −58% in EMs (AUC ratio 2.38×), −23% in IMs. Ki ≈ 0.2/1.38 = 0.145 µM. US label: halve aripiprazole dose with strong CYP2D6 inhibitors.Tramadol (warn): CYP2D6 inhibition (reduces M1 activation). Laugesen 2005 (PMID:15903129) n=16 EMs, tramadol 150 mg ± paroxetine 20 mg/d × 3d: parent (+)-AUC +37% (P=.001), (-)-AUC +32%; active M1 (+)-AUC −67% (P=.0004), (-)-AUC −40%. Ki ≈ 0.2/0.37 = 0.54 µM (parent basis). Reduced opioid analgesia is the dominant clinical concern.Carvedilol (caution): CYP2D6 inhibition (R-enantiomer; the β-active eutomer). Stout 2010 (PMID:20705902) verbatim: "AUC increased significantly with paroxetine coadministration, approximately 2.5-fold and 1.9-fold for the R and S enantiomers, respectively". 12 healthy volunteers, single 12.5 mg PO carvedilol ± paroxetine 10 mg bid, 2-phase crossover. Ki ≈ 0.2/(2.5-1) = 0.133 µM (R basis). No HR/BP/PR changes in healthy normotensives, but the 2.5× exposure is plausibly relevant in HF patients on chronic therapy.Pathways It Modulates Chemical Identifiers PubChem CID: 43815 Formula: C19H20FNO3Molecular weight: 329.37 g/molInChIKey: AHOUBRCZNHFOSL-YOEHRIQHSA-NSMILES: C1CNC[C@H]([C@@H]1C2=CC=C(C=C2)F)COC3=CC4=C(C=C3)OCO4References Directory Compounds Registry Human Biology Hub