Transplacental transfer of amitriptyline and nortriptyline in isolated perfused human placenta

Rationale: Although tricyclic antidepressants (TCAs) have gained wide accep tance for use in the treatment of depression in pregnant women, their pharm acokinetics during pregnancy have been poorly characterized. The aim of the present study was to investigate the transplacental transfer of amitriptyl ine (AMI) and its main active metabolite nortriptyline (NOR) in isolated pe rfused human placenta. Methods: Nine term human placentae were obtained imm ediately after delivery with maternal consent and a 2-h non-recirculating p erfusion of a single placental cotyledon was performed. AMI (200 ng/ml) and NOR (150 ng/ml), with antipyrine as a reference compound, were added to th e maternal reservoir and their appearance to the fetal circulation was foll owed for 2 h. AMI and NOR concentrations were measured by high performance liquid chromatography (HPLC) and antipyrine concentrations spectrophotometr ically. Results: The mean (SD) transplacental transfers (TPTss%) for AMI an d NOR were 8.2 (2.3)% and 6.5 (1.8)%, respectively, calculated as the ratio between the steady-state concentrations in fetal venous and maternal arter ial sides. The TPTs of AMI and NOR were 81% and 62% of the freely diffusabl e antipyrine. The absolute fraction of the dose that crossed the placenta ( TPTA) was moderately, but significantly higher for AMI (7.7%) than for NOR (5.7%) (P=0.037). In all perfusions, steady state at the fetal side was rea ched by 30 min for AMI and by 50 min for NOR in the fetal side. The viabili ty of the placentae was retained during the 2-h perfusion, as evidenced by unchanged FH of the perfusate and by stable perfusion pressures in fetal ar tery and stable antipyrine transfer. Conclusions: Both AMI and NOR cross th e human placenta. However, the fetal exposure with NOR may be somewhat smal ler compared with AMI, probably due to the higher lipophilicity of AMI.