Enantioselectivity of thiopental distribution into the central neural tissue of rats: an interaction with halothane.

Abstract

Thiopental is a racemate. In this study, we examined whether thiopental total body clearance and its distribution into central nervous system (CNS) tissue of rats was enantioselective. Rats, either anesthetized with halothane or conscious and restrained, were infused to stepwise steady-state targets of 5, 10, and 20 microg/mL thiopental by computer-controlled infusions. Serial arterial plasma and steady-state samples of brain and spinal cord were assayed enantiospecifically for thiopental. In both groups, concurrent total and unbound plasma concentrations of S-thiopental were approximately 10%-20% higher than those of R-thiopental, corresponding to its higher clearance. CNS tissue concentrations of S-thiopental were approximately 20% higher than those of R-thiopental. Spinal cord to plasma distribution coefficients were approximately 2 x those in the brain, with relative distribution coefficients approximately 10% greater for R-thiopental in both tissues. Plasma concentrations and distribution coefficients of both enantiomers were approximately 10%-20% lower in the halothane-anesthetized group, with a slightly greater effect on R-thiopental distribution. We conclude that the total body clearance of R-thiopental > S-thiopental, that halothane enantioselectively reduces the relative uptake of R-thiopental into brain tissue, and that composition is important in determining the CNS tissue concentrations of thiopental. The reported higher potency of S-thiopental did not seem to be due to its greater distribution into CNS tissues. Because thiopental is a mixture of two forms (termed R-and S-enantiomers), correct interpretation of its distribution into, and clearance from, the body requires knowledge about both enantiomers. In this study, performed in rats, we showed that the two enantiomers of thiopental differed significantly, with the R-enantiomer having the preferred profile.