Gender Differences in Pharmacokinetics of Fluoxetine in Newborn Lambs up to 1 Month of Age

The disposition of many drugs in infant life is not well studied. Drug therapy is commonly used in newborns and neonates, but drug administered to the mother during the perinatal period and passively transferred to the fetus in utero constitutes a major route of drug exposure in newborns. In utero, the fetus has maternal routes for drug disposition, however after birth, newborns must rely on their own immature mechanisms. Therefore, a thorough understanding of the ontogeny of drug metabolizing pathways is essential to determine the development of these clearance mechanisms from birth to adult life with the goal of providing clinicians with guidelines for optimal drug dosing.

In this study, sheep are used to determine the pharmacokinetics of the commonly used antidepressant fluoxetine at  ~ 3 and 10 days, and 1 month of age. Under isoflurane anesthesia and aseptic surgical techniques, heparin bonded polyurethane catheters were implanted in a carotid artery and jugular vein in lambs at 2 days of age. Racemic fluoxetine (1mg/kg) was administered as an IV bolus injection and arterial blood samples were (2ml) collected at 5, 15, 30, 45, 60 min., and 2, 4, 6, 9, 12, 24, 36, 48, 60, and 72 hours. Plasma was separated and stored at -80^oC until analysis with a validated stereoselective LC/MS/MS assay.¹ Pharmacokinetic parameters calculated include AUC, elimination half-life, clearance, volume of distribution, and mean residence time.

Fluoxetine is primarily metabolized by the enzyme CYP2D6, which is minimally expressed in human and sheep fetuses and progressively develops after birth. The drug is also a chiral compound and exhibits stereoselective disposition with the levels of the S isomer being higher than the R isomer.

Our results indicate that in terms of age, there is no statistical difference in the pharmacokinetic parameters at ~3 and 10 days, and 1 month of age; however, when adult sheep data from our previous study (Kim et al, 2004)² is considered, the pharmacokinetic parameters of the adult sheep are significantly different from those of the lambs. At each age group and for both genders, stereoselective disposition of fluoxetine was observed in AUC, elimination half-life, volume of distribution, clearance, and mean residence time. There appears to be statistically significant gender differences in the pharmacokinetic parameters at ~3 and 10 days, and 1 month of age. In general, the data suggests that female lambs have a greater metabolic capacity for fluoxetine than male lambs. For example, the gender differences in AUC for S-fluoxetine is shown in the following graph:

1.    Chow TW et al. A Validated Enantioselective Assay for the Simultaneous Quantitation of (R)-, (S)-fluoxetine and (R)-, (S)-norfluoxetine in Ovine Plasma Using Liquid Chromatography with Tandem Mass Spectrometry (LC/MS/MS). J. Chromatogr. B 879 (2011) 349.

2.    Kim, J. Phd Thesis, The University of British Columbia (2000).