Abstract

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 μg/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→∞ WM/AUC^0→∞serum = 18.00 μg ml⁻¹ h/32.67 μg 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 μg/ml) and WM (1.2 μg/ml)–low, but the AUC^0→∞ was large (25.55 μg ml⁻¹ in serum and 57.53 μg 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.