Pharmacokinetics of all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in plasma and brain of Rat.
We have measured the pharmacokinetics of three retinoids, all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in rat blood and rat brain [especially white matter (WM) and gray matter (GM)] to help select retinoids for treating human malignant glioma. All-trans retinoic acid permeated well into the WM, giving peak concentration in WM of 25.7 microg/g, 6 to 7 times higher than the peak serum concentration. There was less 13-cis retinoic acid in WM: area under the curve (AUC)(0-->infinity) WM/AUC(0-->infinity) serum = 18.00 microg ml(-1) h/32.67 microg ml(-1) h. The ratio WM/GM was over 1 for these two compounds, but the half-lives were short in the serum and cerebral tissue (0.57-1.02 h). Fenretinide had different pharmacokinetics: the peak concentrations were in serum (1.7 microg/ml) and WM (1.2 microg/ml)-low, but the AUC(0-->infinity) was large (25.55 microg ml(-1) in serum and 57.53 microg ml(-1) in WM) due to its long elimination half-life (13.78 h in serum and 17.77 h in WM). These findings provide information that may be used to select a retinoid and establish therapeutic regimens that provide optimal efficacy with minimal toxicity.
Le Doze
F
F
Laboratory of Pharmacology, Unit of Neurology Dejerine, Unité Propre de Recherche de l'Enseignement Supérieur-Equipe d'accueil 2609, France.
Debruyne
D
D
Albessard
F
F
Barre
L
L
Defer
G L
GL
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D017313:Fenretinide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D007274:Injections, Intraperitoneal; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014212:Tretinoin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D017313:Fenretinide; D014212:Tretinoin