Session 9 : Pharmacocinétique
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
*Service de Pharmacologie, **Service de Neurologie Dejerine, CHU, avenue de la Côte de Nacre, 14033 Caen Cedex, France
In order to assess the distribution 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 corpus callosum) and GM (from frontal cortex) after i.p. injection 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 point). Samples were mixed in buffer, precipitated with acetonitrile and analysed by reversed phase 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 distribution 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 distribution of retinoids in rat may show consistant pharmacokinetic differences between the molecules and within brain tissues. These differences might be relevant in order to optimise drug administration in man and need to be confirmed with human neurosurgical material.
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 Bordeaux Cedex and *Laboratory of Neurosciences, CNRS URA 339, University of Bordeaux I, 33405 Talence Cedex, France
The diffusion of seven arylpropionic acid NSAlDs into the cerebrospinal fluid (CSF) has been investigated in male Wistar rats by means of quantitative structure activity relationship (QSAR) studies. After intraperitoneal administration of each drug (5mg/kg), blood and CSF amples were collected at different times (0.5, 1, 3 and 6 hours). The total (CT) and free (CF) plasma concentrations and the concentrations in the CSF (CCSF) were measured by a reversed-phase high performance liquid chromatographic (RP-HPLC) method. The area under the curve of the free plasma (AUCF) and CSF (AUCCSF) concentrations were calculated according to the trapezoidal rule. The AUCCSF:AUCF ratio (RAUC) was chosen as an index of drug penetration into CSF. The fraction bound to plasma 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 plasma levels then decreased from a ratio of 5 in 15 minutes. After a moderate rebound in plasma 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 normal MTX elimination. Thus, CPDG2 may constitute an alternative pathway for the management of MTX intoxication.
POPULATION PHARMACOKINETIC OF A LOW MOLECULAR WEIGHT HEPARIN (NADROPARIN CALCIUM) IN INFANTS AND CHILDREN AFTER CARDIAC SURGERY
Patrick Mismetti, Silvy Laporte, Pascal Piquet*, Sylvie Doubine*, Anita Touchot** and Hervé Decousus*.
Unité Pharmacologie Clinique, Hôpital Bellevue St-Etienne; *Laboratoire d’Hémostase and **Pédiatrie, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, FRANCE.
– The aim of this study was to determine the population pharmacokinetic parameters of a low-molecular-weight heparin (Nadroparin Calcium, Fraxiparine