Stereoselective disposition of fluoxetine and norfluoxetine during pregnancy and breast-feeding.
OBJECTIVE
To compare the disposition of fluoxetine and norfluoxetine enantiomers in the mother, foetus and infant.


METHODS
Blood from pregnant women taking fluoxetine (n = 9), during pregnancy was sampled in the third trimester and at delivery (maternal and cord venous blood), and from the infants 48 h after delivery. The subset of these women who were breastfeeding, plus additional subjects recruited in the postpartum period, were studied further, and maternal and infant blood, and breast milk was sampled between 6 days and 11 months (n = 23). Drug and metabolite concentrations were measured using gas chromatography/mass spectrometry or liquid chromatography, tandem mass spectrometry.


RESULTS
There was a high correlation between maternal and foetal (cord blood) fluoxetine and norfluoxetine enantiomers (r(2)-0.9), the mean foetal/maternal ratios (95% confidence intervals) being 0.91 (0.61, 1.02) and 1.04 (0.93, 1.05), for fluoxetine and norfluoxetine, respectively. In 2 day old infants exposed to the drug in utero, the fluoxetine and norfluoxetine plasma concentrations were the same as in cord blood at delivery. Over the next 2 months, the plasma concentrations in the infants fell progressively. Stereoselective disposition of both the drug and metabolite in the mother, foetus, infant and breast milk was observed. The S : R ratios in the foetus and newborn ( approximately 3) were significantly higher than in the serum ( approximately 2) or breast milk ( approximately 1.9) of the mothers, resulting in greater exposure of the foetus and infants to the biologically active enantiomers, particularly S-norfluoxetine.


CONCLUSIONS
Foetal and infant exposure to fluoxetine and norfluoxetine is enhanced by their stereoselective disposition in the mother, foetus, breast milk and infant. Increased exposure may also result from decreased metabolism of the drug in the foetus and neonate.
Kim
John
J
Department of Psychiatry, University of British Columbia.
Riggs
K Wayne
KW
Misri
Shaila
S
Kent
Nancy
N
Oberlander
Tim F
TF
Grunau
Ruth E
RE
Fitzgerald
Colleen
C
Rurak
Dan W
DW
D000328:Adult; D000375:Aging / Q000097:blood; D018687:Antidepressive Agents, Second-Generation / Q000097:blood* / Q000627:therapeutic use; D001942:Breast Feeding; D003865:Major Depressive Disorder / Q000097:blood* / Q000188:drug therapy; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000097:blood* / Q000627:therapeutic use; D006801:Humans; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange; D008895:Milk, Human / Q000737:chemistry; D049590:Postpartum Period / Q000097:blood; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood* / Q000188:drug therapy; D011446:Prospective Studies; D013237:Stereoisomerism
D018687:Antidepressive Agents, Second-Generation; D005473:Fluoxetine; C036139:norfluoxetine