Considering that fluoxetine (FLX) is used to treat depressive states during pregnancy and that it is a cytochrome P450 (CYP)2D6 inhibitor, which is involved in the metabolism of both of its enantiomers, this study aims to describe the enantioselective distribution and metabolism of FLX and of its metabolite norfluoxetine (NorFLX) following a single oral dose. Nine healthy pregnant women received 20 mg FLX at 32 weeks of gestation and later at the day of delivery. The apparent clearance of (S)-(+)-FLX (1.45 vs. 0.66 L/hour/kg) and the area under the plasma concentration vs. time curve (AUC) of the (S)-(+)-NorFLX (AUC 0-∞ 942.7 vs. 498.6 ng hour/mL) were higher (P < 0.05) than those of the respective (R)-(−) enantiomers, indicating that the (S)-(+)-FLX enantiomer is preferentially metabolized to (S)-(+)-NorFLX. The placental transfer (umbilical vein/maternal vein) of FLX and NorFLX is low (30-40%), with the predominant transfer of (S)-(+)-FLX (44 vs. 33%). The distribution of the enantiomers of FLX and NorFLX to amniotic fluid is low (< 10%).

The present study assessed the effect of systemic lupus erythematosus (SLE) activity, a chronic and inflammatory autoimmune disease, on the sinusoidal uptake transporter OATP1B1 using atorvastatin (ATV) as a probe drug. Fifteen healthy subjects, 13 patients with controlled SLE (SLEDAI 0–4), and 12 patients with uncontrolled SLE (SLEDAI from 6 to 15), all women, were investigated. Apparent total clearance of midazolam (MDZ), a marker of CYP3A4 activity, did not vary among the three investigated groups. The controlled and uncontrolled SLE groups showed higher plasma concentrations of MCP‐1 and TNF‐α, while the uncontrolled SLE group also showed higher plasma concentrations of IL‐10. The uncontrolled SLE group showed higher area under the curve (AUC) for ATV (60.47 (43.76–83.56) vs. 30.56 (22.69–41.15) ng⋅hour/mL) and its inactive metabolite ATV‐lactone (98.74 (74.31–131.20) vs. 49.21 (34.89–69.42) ng⋅hour/mL), and lower apparent total clearance (330.7 (239.30–457.00) vs. 654.5 (486.00–881.4) L/hour) and apparent volume of distribution (2,609 (1,607–4,234) vs. 7,159 (4,904–10,450) L), when compared to the healthy subjects group (geometric mean and 95% confidence interval). The pharmacokinetics of ATV and its metabolites did not differ between the healthy subject group and the patients with controlled SLE group. In conclusion, uncontrolled SLE increased the systemic exposure to both ATV and ATV‐lactone, inferring inhibition of OATP1B1 activity, once in vivo CYP3A4 activity assessed by oral clearance of MDZ was unaltered. The inflammatory state, not the disease itself, was responsible for the changes described in the uncontrolled SLE group as a consequence of inhibition of OATP1B1, because systemic exposure to ATV and its metabolites were not altered in patients with controlled SLE.

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