Diazepam transport across the blood-brain barrier

Abstract

Male rats (Wistar-Imamichi strain) at 21 days of age when ontogenetic development of the brain would be completed were used, and the pharmacokinetics of diazepam after intraperitoneal administration was determined on the theoretical basis established for analyzing the absorption process with the aid of a computer. Unlabeled diazepam of 0.9 mg/kg was injected with a trace amount of [N-methyl-3H]-diazepam, and the drug concentrations in the blood and the brain were measured at various time intervals. A two-compartment open model was applied, and the elimination rate constant was first determined from the data obtained in its later phase, and the absorption rate constant was calculated utilizing the slope value at zero time in the arranged kinetic equation, and lastly the distribution rate constant was determined so as to give the least square for the theoretical curve. The specific rate constants for absorption, distribution (k12 and k2i), and elimination were 0.16, 0.015 and 0.14, and 0.013/min, respectively. A full description of the drug concentration in the central compartment as a function of time made it possible to solve the equation for drug transfer between the blood and the brain. The computed rate constants were 4.5 and 2.7/min for the k’12 and klι on the average of five regions in the brain. The results suggested that there may exist no barrier system between the blood and the brain tissues to diazepam.