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 retinoi c acid, 13-cis retinoic acid, and fenretinide in rat blood and rat brain [e specially 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 mu g/g, 6 to 7 times higher than the peak serum concentration. There was less 13-cis retinoic ac id in WM: area under the curve (AUC)(0-->infinity) WM/AUC(0-->infinity) ser um = 18.00 mu g ml(-1) h/32.67 mu g ml(-1) h. The ratio WM/GM was over 1 fo r these two compounds, but the half-lives were short in the serum and cereb ral tissue (0.57-1.02 h). Fenretinide had different pharmacokinetics: the p eak concentrations were in serum (1.7 mu g/ml) and WM (1.2 mu g/ml)-low, bu t the AUC(0-->infinity) was large (25.55 mu g ml(-1) in serum and 57.53 mu g 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 sel ect a retinoid and establish therapeutic regimens that provide optimal effi cacy with minimal toxicity.