Contribution and limit of the model of perfused cotyledon to the study of placental transfer of drugs. Example of a protease inhibitor of HIV: nelfinavir.
OBJECTIVE
The perfused cotyledon model is a very useful method to study placental transfer of drugs. Here we studied placental transfer of the human immunodeficiency virus protease inhibitor nelfinavir using the non-recirculating dual human placental perfusion with a main goal to determining the clearance index of nelfinavir as related to maternal concentrations, and analyze the conditions under which ex vivo and in vivo data can be correlated.


METHODS
Thirteen human cotyledons, obtained after uneventful term pregnancies, were perfused in an open double circuit with nelfinavir (320-4436 microg/l) and a freely diffusing marker antipyrine 20 mg/l, in the presence of an albumin concentration of 2 g/l. Drug concentrations were determined by high-performance liquid chromatography.


RESULTS
The mean clearance index of nelfinavir was very weak when maternal concentrations were under 500 microg/l (0.03+/-0.05). For maternal concentrations above 1200 microg/l, the mean fetal transfer rate was 14+/-3.4%, the mean clearance index was 0.39+/-0.10 and the fetal concentrations were between 133 and 671 microg/l. There was a good correlation between maternal and fetal concentrations (r=0.86; p<0.001).


CONCLUSIONS
Our study with nelfinavir has achieved a good correlation between ex vivo and in vivo data. Our results also indicate that studies must be conducted under well defined conditions to obtain accurate and comparable data, underlining the fact that the ex vivo perfused cotyledon remains difficult to standardize as a model system.
Gavard
Laurent
L
Department of Clinical Pharmacy, University Paris-Sud 11, IFR141, School of Pharmacy, Châtenay-Malabry, France. lgavard@aol.fr
Beghin
Delphine
D
Forestier
François
F
Cayre
Yvon
Y
Peytavin
Gilles
G
Mandelbrot
Laurent
L
Farinotti
Robert
R
Gil
Sophie
S
D005260:Female; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D008431:Maternal-Fetal Exchange; D019888:Nelfinavir / Q000493:pharmacokinetics*; D010477:Perfusion; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding
D017320:HIV Protease Inhibitors; D019888:Nelfinavir