Place des nouvelles technologies pour les etudes pharmacocinetiques de la femme enceinte et de l'allaitement

Modifications in various physiological functions occur during pregnancy and lactation period. These alterations induce variations of the pharmacokinetic parameters of drugs. The safety rule is to avoid prescription during pregnancy. Nevertheless, several diseases require continuous treatment. Modifications of drug metabolism need to be investigated in order to limit the risks for both the mother and the newborn. Today, it is difficult to include pregnant or nursing women into clinical trials for evident ethical reasons. Functional and pharmacological studies require a general and adapted methodology, which include non-invasive methods and detailed protocols, for the production of a large data base for clinicians and investigators. In this context, stable isotopes and isotopic mass spectrometry are of interest. Actually, stable isotopes are excellent biological tracers, free of any radioactivity and toxicity.;The main goal of the thesis is to develop a general and non-invasive methodology using stable isotopes and mass spectrometry for the evaluation of hepatic drug metabolizing enzymes during pregnancy and for the study of drugs transfer into breast milk during lactation.;A clinical protocol and a general method of analysis by solid phase extraction and gas chromatography-mass spectrometry were developed to study the transfer of drugs into breast milk. The protocol is designed to control the collection of milk sample and to gather all the various information and parameters needed to perform comprehensive pharmacokinetic analyses. The analytical method allows the determination of various drugs in milk and is easily and rapidly adaptable to other drugs and their metabolites. The use of these modern tools assures that the interpretation of experimental data is independent from the context of the study.;For the evaluation of hepatic drug metabolizing enzymes (CYP450), the 13C-caffeine breath test and the urinary metabolic ratios of 13C-caffeine were both validated as indicators of the variations of CYP1A2 activity. The use of labelled caffeine for the measurement of metabolic ratios specifically eliminates potential interference from caffeine's metabolites relating to diet, thus improving the overall selectivity of the test.;The breath test is related to the metabolism of caffeine by CYP1A2 whereas metabolic ratios are related to various metabolic pathways and can be used as indicators to assess the activity of others enzymes. These non-invasive tests are of relevant interest for studying the longitudinal variations of CYP1A2 activity along pregnancy and potentially identify and anticipate damages due to diseases. These tests can be adapted to other substrates in order to determine other CYP450 activities.;In conclusion, isotopic analysis and related technologies based on the use of stable isotopes are innovative tools that were shown to improve the efficiency of clinical protocols, especially when protected populations such as pregnant women or nursing mothers are included.