No abstract

Sertraline is a naphthalenamine derivative with the predominant pharmacological action of inhibiting presynaptic reuptake of serotonin from the synaptic cleft. It was initially marketed for the treatment of major depressive disorder and is now approved for the management of panic disorder, obsessive-compulsive disorder and post-traumatic stress disorder. Sertraline is slowly absorbed following oral administration and undergoes extensive first-pass oxidation to form N-desmethyl-sertraline, a weakly active metabolite that accumulates to a greater concentration in plasma than the parent drug at steady state. Sertraline is eliminated from the body by other metabolic pathways to form a ketone and an alcohol, which are largely excreted renally as conjugates. The elimination half-life of sertraline ranges from 22-36 hours, and once-daily administration is therapeutically effective. Steady-state plasma concentrations vary widely, up to 15-fold, in patients receiving usual antidepressant dosages between 50 and 150 mg/day. However, only sparse data have been published that support useful correlations between sertraline plasma concentrations and therapeutic or adverse effects to justify therapeutic drug monitoring. Sertraline has minimal inhibitory effects on the major cytochrome P450 enzymes, and few drug-drug interactions of clinical significance have been documented. Like other selective serotonin reuptake inhibitors, sertraline is well tolerated in therapeutic dosages and relatively safe in overdosage.

Glucuronidation is a phase II metabolic process and one of the most common pathways in the formation of hydrophilic drug metabolites. At least 33 families of uridine diphosphate-glucuronosyltransferases have been identified in vitro, and specific nomenclature similar to that used to classify the cytochrome (CYP) P450 system has been established. The UGT1 and UGT2 subfamilies represent the most important of these enzymes in human drug metabolism. Factors affecting glucuronidation include the following: cigarette smoking, obesity, age, and gender. In addition, several drugs have been found in vitro to be substrates, inhibitors, or inducers of UGT enzymes. Induction or inhibition of both UGT and CYP isoforms may occur simultaneously. Some important drug interactions involving glucuronidation have been documented and others can be postulated. This review summarizes the relevant literature pertaining to drug glucuronidation and its implications for clinical psychopharmacology.

The selective serotonin reuptake inhibitors (SSRIs) paroxetine, sertraline, and fluoxetine have varying degrees of potency in inhibiting the hepatic cytochrome P450 (CYP) 2D6 enzyme. However, the time course for maximum inhibition to occur or for inhibition to dissipate when dosing is discontinued, requires clarification. In an open label, parallel group study of 45 healthy volunteers, the time course of CYP2D6 inhibition of the above SSRIs was evaluated. Subjects were randomized to receive paroxetine at 20 mg/day for 10 days; sertraline at 50 mg/day for 3 days, followed by sertraline at 100 mg/day for 10 days; or fluoxetine at 20 mg/day for 28 days. CYP2D6 activity was assessed using the dextromethorphan metabolic ratio (DMR) on antidepressant days 5 and 10 for sertraline and paroxetine and at weekly intervals for fluoxetine. Following SSRI discontinuation, calculation of a CYP2D6 inhibition half-life (t(1/2)inh) revealed the time course of fluoxetine inhibition (t(1/2)inh = 7.0 +/- 1.5 days) to be significantly longer than either paroxetine (t(1/2)inh = 2.9 +/- 1.9) or sertraline (t(1/2)inh = 3.0 +/- 3.0) (p < 0.01), but the latter were not significantly different from each other (p > 0.05). Time for the extrapolated DMR versus time log-linear plots to return to baseline was significantly different between fluoxetine (63.2 +/- 5.6 days) and both paroxetine (20.3 +/- 6.4 days) and sertraline (25.0 +/- 11.0 days) (p < 0.01), making the rank order (from longest to shortest) of time for CYP2D6 inhibition to dissipate: fluoxetine > sertraline >or= paroxetine. Differences between mean baseline DMR values and measured values obtained after drug discontinuation for each drug group became nonsignificant on discontinuation day 5 for both paroxetine and sertraline and on discontinuation day 42 for fluoxetine. These data define the time course of a persistent effect that fluoxetine, sertraline, and paroxetine have on CYP2D6 following drug discontinuation and should be considered when initiating therapy with a CYP2D6 substrate.

An antidepressant for use in the patient receiving concomitant drug treatment, over-the-counter medications, or herbal products should lack cytochrome P-450 (CYP) 3A4 inductive or inhibitory activity to provide the least likelihood of a drug-drug interaction. This study addresses the potential of 4 diverse antidepressants (venlafaxine, nefazodone, sertraline, and fluoxetine) to inhibit or induce CYP3A4. In a 4-way crossover design, 16 subjects received clinically relevant doses of venlafaxine, nefazodone, or sertraline for 8 days or fluoxetine for 11 days. Treatments were separated by a 7- to 14-day washout period and fluoxetine was always the last antidepressant taken. CYP3A4 activity was evaluated for each subject at baseline and following each antidepressant using the erythromycin breath test (EBT) and by the pharmacokinetics of alprazolam (ALPZ) after 2-mg dose of oral ALPZ. Compared to baseline, venlafaxine, sertraline, and fluoxetine caused no apparent inhibition or induction of erythromycin metabolism (P > 0.05). For nefazodone, a statistically significant inhibition was observed (P < 0.0005). Nefazodone was also the only antidepressant that caused a significant change in ALPZ disposition, decreasing its area under the concentration-versus-time curve (AUC; P < 0.01), and increasing its elimination half-life (16.4 vs. 12.3 hours; P < 0.05) compared with values at baseline. No significant differences were found in the pharmacokinetics of ALPZ with any of the other antidepressants tested. These results demonstrate in vivo that, unlike nefazodone, venlafaxine, sertraline, and fluoxetine do not possess significant metabolic inductive or inhibitory effects on CYP3A4.