The Effects of Desvenlafaxine and Paroxetine on the Pharmacokinetics of the Cytochrome P450 2D6 Substrate Desipramine in Healthy Adults

Abstract

The potential for cytochrome P450 (CYP) 2D6 substrates to interact with desvenlafaxine (administered as desvenlafaxine succinate) and paroxetine was evaluated. In an open-label, crossover study, 20 healthy volunteers (aged 21-50) were randomized to 2 series of 9 days each of desvenlafaxine (100 mg/d) or paroxetine (20 mg/d), separated by a 5-day washout. The CYP2D6 substrate desipramine (50 mg) was administered alone on day 1 and coadministered on day 6 of dosing with either desvenlafaxine or paroxetine. CYP2D6 genotype was determined at baseline. Based on least squares geometric mean ratios between reference (desipramine alone) and test treatments, desvenlafaxine produced minor increases in desipramine area under the plasma concentration versus time curve (AUC; 36%) and peak plasma concentration (C(max); 30%) (vs paroxetine: 419%, 90%, respectively; both P < .001). Desvenlafaxine produced little change in 2-hydroxydesipramine AUC (16% increase) and C(max) (0%) versus paroxetine (18% and 82% decreases, respectively; P = .008, P < .001, respectively), indicating that desvenlafaxine, especially at the recommended therapeutic dose of 50 mg/d for major depressive disorder in the United States, has little potential to interact with CYP2D6 substrates.

Assessing Risks and Benefits of Nonhormonal Treatments for Vasomotor Symptoms in Perimenopausal and Postmenopausal Women

“…80 In vitro data indicate that desvenlafaxine has negligible effect on CYP450 enzymes or on p-glycoprotein activity and, consequently, is believed to have a minimal likelihood of inducing drug interactions. [89][90][91] Gabapentin. Gabapentin is a c-aminobutyric acid analogue indicated for the treatment of partial seizures and postherpetic neuralgia.…”

Effect of Food on the Pharmacokinetics of Desvenlafaxine in Healthy Subjects

“…Phase I hepatic metabolism of desvenlafaxine appears to play a small role in its elimination, marked by metabolism to N,O-didesmethylvenlafaxine by the cytochrome P450 (CYP450) 3A4 pathway [5]. Because desvenlafaxine is primarily metabolized via glucuronidation, and clinical reports have shown that desvenlafaxine exerts minimal effects on the activities of the CYP450 enzymes or p-glycoprotein, the potential ability of other drugs to alter desvenlafaxine metabolism is low [6][7][8][9][10].…”

Drug Interactions in the Treatment of Depression in Patients Receiving β-Blocker Drugs

“…Paroxetine is a potent inhibitor of CYP2D6, 10,11 the enzyme that plays a major role in the metabolism of metoprolol. 3 This explains why paroxetine increases pharmacokinetic indices of exposure to metoprolol and, hence, the cardiovascular effects of metoprolol.…”

“…It is apparent that most of the commonly used β-blockers are either metabolized by CYP2D6 or eliminated by renal excretion 3,[12][13][14][15][16][17][18][19] ; thus, an awareness of which commonly used antidepressants significantly inhibit CYP2D6 10,11,[20][21][22][23][24][25] will warn clinicians about the risk of a potential drug interaction. Table 3 also lists antidepressants that are mild inhibitors of CYP2D6 10,23,25,26,[29][30][31] ; these are probably associated with lower risk of CYP2D6 drug interactions at usual clinical doses.…”