Pharmacokinetics of thiopental enantiomers during and following prolonged high-dose therapy

Background: Thiopental is used as a racemate; however, this is not generall y recognized. During conditions of prolonged high-dose therapy, the pharmac okinetics of thiopental may become nonlinear, but whether this derives from one or both enantiomers has not been evaluated, The authors determined the pharmacokinetics of R- and S-thiopental and serum concentrations of R- and S-pentobarbital from prolonged high-dose infusion of thiopental for neurop rotection. Methods: Twenty patients received a mean thiopental dose of 41.2 g over a m ean duration of 95 h, R- and S-thiopental enantiomer serum concentration-ti me data from 18 patients were fitted with two models: a linear one-compartm ent model with first-order output, and a nonlinear one-compartment model wi th Michaelis-Menten output. Results: Nonlinear models were preferred in 16 of 18 patients. Paired analy sis indicated that steady state clearance (Cl-ss) and volume of distributio n (V-d) were higher for R-thiopental (0.108 vs. 0.096 l/min, P < 0.0001: an d 313 vs. 273 1, P < 0.0005, respectively); maximal rate of metabolism (V-m ) was higher for S- than for R-thiopental (1.01 vs. 0.86 mg . l(-1) . h(-1) , P = 0.02); elimination half-lives did not differ (14.6 vs. 14.7 h, P = 0. 8); unbound fractions (f(u)) of R- and S-thiopental were 0.20 and 0.18, res pectively, P < 0.0001). The differences in mean Cl-ss, V-d and V-m were not significant when adjusted by f(u). Plasma concentrations of R- and S-pento barbital were relatively small and unlikely to be of clinical significance. Conclusion: The pharmacokinetics of R- and S-thiopental became nonlinear at these doses. The pharmacokinetic differences between R- and S-thiopental, although small, were statistically significant and were influenced by the h igher f(u) of R-thiopental.