Disposition of chiral and racemic fluoxetine and norfluoxetine across childbearing.

In the United States, 14.5% of women develop a new episode of depression during pregnancy or the first 3 months after childbirth.1 The prevalence increases across gestation with rates in the first, second, and third trimesters of 7.4% (95% confidence interval [CI], 2.2%–12.6%), 12.8% (10.7%–14.8%), and 12.0% (7.4%–16.7%), respectively.2 The serotonin reuptake inhibitor (SRI) is the most commonly prescribed antidepressant class during pregnancy; each year, 92,000 (2.8%) pregnant women receive an SRI agent (Birth Defects Prevention Study, 1997–2002).3 Of the SRI compounds, fluoxetine is a frequent choice for the management of major depression, obsessive compulsive disorder, panic disorder, bipolar depression, and bulimia nervosa. However, limited pharmacologic data are available for the disposition of fluoxetine across pregnancy and early postpartum.4,5 The dose requirement for antidepressant drugs taken during pregnancy may increase for several reasons. During pregnancy, hepatic enzyme induction accelerates drug metabolism to increase dose requirements.4–7 Examples include nortriptyline,6 which is a substrate of cytochrome (CYP) 2D6; citalopram, a substrate of 2C19, 3A4, and 2D67–10; and sertraline, a substrate of CYP 2D6, 2C9, 2B6, 2C19, and 3A4.10–14 High steroid hormone levels also induce CYP activity.15 Other changes in pregnancy may increase drug clearance; the expanded plasma volume and total body water augment the volume of distribution of drugs. Altered hepatic perfusion (increased portal venous return and unchanged hepatic arterial blood flow),16 reduced plasma protein (albumin) levels that lead to decreased drug binding, increased glomerular filtration and renal excretion17,18 may give rise to increased dose requirements. These changes may explain the intraindividual variability in treatment response during the childbearing period.19 N-demethylation of the active parent compound fluoxetine (FLX) produces the active metabolite norfluoxetine (NorFLX), hepatic CYP 2D6, 2C9, 3A4, and, to a lesser degree, 2C19 demethylate fluoxetine.20–23 The parent compound comprises a 50:50 (racemic) mixture of S and R isomers. The S-isomers are metabolized mainly by CYP 2D6,21,24,25 and the R-isomers are metabolized mainly by 2D6 and 2C9.20 S-NorFLX, S-FLX, and R-FLX are the moieties26 that contribute to the potency of fluoxetine.27,28 The expected half-life of the parent compound FLX is 2 to 4 days, and that of the metabolite NorFLX is 7 to 15 days.28–30 The parent compound FLX reaches steady-state concentration within 23 days.21 In patients who are slow metabolizers or patients who receive doses higher than 40 mg daily, the half-lives of FLX and NorFLX are prolonged (S- and R-FLX, 6.1 and 9.5 days; S- and R-NorFLX, 17.4 and 6.9 days).24,30 Correlations between the dose and steady-state concentrations indicate linear pharmacokinetics (PK) at doses less than 40 mg daily.29 At doses of 40 to 60 mg daily, the PK is no longer linear,29 although saturation kinetics at higher doses have not been detected.31 We explored the dose-corrected plasma chiral and racemic fluoxetine, norfluoxetine levels (level/dose [L/D]), and depression scores of women across gestation, delivery, and postpartum. We assessed changes in the chiral and racemic fluoxetine, norfluoxetine, and fluoxetine/norfluoxetine levels. Because the metabolite R-norfluoxetine is not active plus the parent compound comprises a 50:50 (racemic) mixture of S- and R-isomers, analysis of the parent drug–metabolite ratios is reasonable to estimate metabolic activity.5,7 We hypothesized that: (1) dose-corrected fluoxetine/norfluoxetine levels would decrease during pregnancy with accelerated drug metabolism, and (2) dose-corrected fluoxetine/norfluoxetine levels would increase after delivery during the brief refractory metabolic state. We explored the association between dose-corrected fluoxetine/norfluoxetine levels and depression scores across pregnancy and postpartum. To our knowledge, there are no previous studies of chiral and racemic fluoxetine/norfluoxetine levels and depression scores across multiple time points during the childbearing period.