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
Received 21 January 2009; received in revised form 1 July 2009; accepted 18 August 2009. published online 01 September 2009.
Abstract
Objectives
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.
Study design
Thirteen human cotyledons, obtained after uneventful term pregnancies, were perfused in an open double circuit with nelfinavir (320–4436μg/l) and a freely diffusing marker antipyrine 20mg/l, in the presence of an albumin concentration of 2g/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 500μg/l (0.03±0.05). For maternal concentrations above 1200μg/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 671μg/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.
aDepartment of Clinical Pharmacy, University Paris-Sud 11, IFR141, School of Pharmacy, Châtenay-Malabry, France
bDepartment of Obstetrics and Gynecology, AP-HP, Louis Mourier Hospital, University Denis Diderot Paris 7, Colombes, France
cRobert Debré Hospital, AP-HP, University Pierre et Marie Curie - Paris 6, UMR 7613 Synthèse, Structure et Fonction de Molécules Bioactives, Paris, France
dDepartment of Pharmacology, AP-HP, Bichat Hospital, University Denis Diderot - Paris 7, Paris, France
eDepartment of pharmacology, AP-HP, Pitié-Salpêtrière Hospital, University Pierre et Marie Curie - Paris 6, Paris, France
Corresponding author at: Faculté de Pharmacie – UPRES EA 2706, Laboratoire de Pharmacie Clinique, 5 rue Jean Baptiste Clément, 92296 Châtenay-Malabry cedex 20, France. Tel.: +33 01 4683 5577; fax: +33 01 4683 5618.
ABSTRACT