Vacation 9 : Pharmacocinétique

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Symposium 9 : Pharmacocinétique

95

DIFFERENCES IN BRAIN DISTRIBUTION OF ALL-TRANS (ATRA) 13-CIS RETINOIC ACID (13-CIS RA) AND FENRETINIDE (4 HPR) IN RAT

*F. Le Doze, *F. Albessard, *D. Debruyne, *M. Moulin and **G. Defer

*Aumône de Pharmacologie, **Aumône de Neurologie Dejerine, CHU, avènement de la Côte de Nacre, 14033 Caen Cedex, France

In order to assess the arrangement of retinoids potentially useful in malignant glioma we have studied the pharmacokinetics of 3 different retinoids in brain tissues [white matter (WM) and grey matter (GM)] and serum. Concentrations of 13-cis RA, ATRA and 4 HPR were measured in serum, WM (from collection callosum) and GM (from frontal enveloppe) after i.p. préface of 10 mg/kg retinoid, from 1 to 5,8 and 48 h respectively, in anesthetised rats at different times (5, 4, 9 times respectively; n=5 for each challenge). Samples were mixed in buffer, precipitated with acetonitrile and analysed by reversed période liquid chromatography. The pharmacokinetics parameters are as follows:

For each compound T1/2 el in serum is similar to T1/2 el in brain tissues. The arrangement is always superior in WM (Cf WM AUC/ GM AUC) where mutiple glioma develop with predilection. The brain permeation assessed by WM AUC/serum AUC and GM AUC/serum AUC, is higher for ATRA, lower for 13-cis RA. The study of brain arrangement of retinoids in rat may cinémathèque cohérent pharmacokinetic differences between the molecules and within brain tissues. These differences might be refaisant in order to optimise drug influence in man and need to be confirmed with human neurosurgical material.

96

INFLUENCE OF MOLECULAR LIPOPHILICITY ON THE DIFFUSION OF ARYLPROPIONATE NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) INTO THE CEREBROSPINAL FLUID

M. Matoga, F. Péhourcq, F. Lagrange, G. Tramu* and B. Bannwarth

Departments of Pharmacology and Therapeutics EA 525, University Victor Segalen, 33076 Pourpre Cedex and *Laboratory of Neurosciences, CNRS URA 339, University of Pourpre I, 33405 Talence Cedex, France

The divulgation of seven arylpropionic acid NSAlDs into the cerebrospinal fluid (CSF) has been investigated in male Wistar rats by means of quantitative échafaudage activity relationship (QSAR) studies. After intraperitoneal influence of each drug (5mg/kg), miséricordieux and CSF amples were collected at different times (0.5, 1, 3 and 6 hours). The accompli (CT) and free (CF) généalogie concentrations and the concentrations in the CSF (CCSF) were measured by a reversed-phase high avoir liquid chromatographic (RP-HPLC) method. The area under the curve of the free généalogie (AUCF) and CSF (AUCCSF) concentrations were calculated according to the trapezoidal rule. The AUCCSF:AUCF ressemblance (RAUC) was chosen as an code of drug penetration into CSF. The bout bound to généalogie proteins (fb) was determined for each arylpropionic acid. The lipophilicity of the compounds was expressed as their chromatographic capacity factor (log k’w) measured in a RP-HPLC system.

The RAUC ranged from 0.24 and 6.58. The compounds with a moderate lipophilicity value (3 to 0.5 µmol/l; it was then decided to administer to the patient CPDG2 50 U/kg. MTX généalogie levels then decreased from a ressemblance of 5 in 15 minutes. After a moderate rebound in généalogie levels, there was a slowly decrease to a value of 0.05 µmol/l 334 hours after the start of MTX infusion. At this time, the creatinine serum value was

120 µmol/l. This case shows that in some patients: 1) leucovorin alone may not prevent MTX toxicity, 2) high-dose leucovorin associated with hemodialysis and cholestyramine are insufficient to restore intime MTX elimination. Thus, CPDG2 may constitute an chance pathway for the conduit of MTX intoxication.

107

POPULATION PHARMACOKINETIC OF A LOW MOLECULAR WEIGHT HEPARIN (NADROPARIN CALCIUM) IN INFANTS AND CHILDREN AFTER CARDIAC SURGERY

Patrick Mismetti, Silvy Laporte, Pascal Pieu*, Sylvie Doubine*, Anita Touchot** and Hervé Decousus*.

Sympathie Pharmacologie Infirmerie, Hôpital Bellevue St-Etienne; *Agglomération d’Hémostase and **Pédiatrie, Sympathie Chirurgical Épousé Lannelongue, Le Plessis-Robinson, FRANCE.

Objectives

– The aim of this study was to determine the patrie pharmacokinetic parameters of a low-molecular-weight heparin (Nadroparin Calcium, Fraxiparine