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Thiopental is used as a racemate; however, this is not generally recognized. During conditions of prolonged high-dose therapy, the pharmacokinetics of thiopental may become nonlinear, but whether this derives from one or both enantiomers has not been evaluated. The authors determined the pharmacokinetics ofR-andS-thiopental and serum concentrations ofR-andS-pentobarbital from prolonged high-dose infusion of thiopental for neuroprotection.Twenty patients received a mean thiopental dose of 41.2 g over a mean duration of 95 h.R-andS-thiopental enantiomer serum concentration–time data from 18 patients were fitted with two models: a linear one-compartment model with first-order output, and a nonlinear one-compartment model with Michaelis-Menten output.Nonlinear models were preferred in 16 of 18 patients. Paired analysis indicated that steady state clearance (Clss) and volume of distribution (Vd) were higher forR-thiopental (0.108vs.0.096 l/min,P< 0.0001; and 313vs.273 l,P< 0.0005, respectively); maximal rate of metabolism (Vm) was higher forS-than forR-thiopental (1.01vs.0.86 mg · l−1 · h−1,P= 0.02); elimination half-lives did not differ (14.6vs.14.7 h,P= 0.8); unbound fractions (fu) ofR-andS-thiopental were 0.20 and 0.18, respectively,P< 0.0001). The differences in mean Clss, Vd and Vm were not significant when adjusted by fu. Plasma concentrations ofR-andS-pentobarbital were relatively small and unlikely to be of clinical significance.The pharmacokinetics ofR-andS-thiopental became nonlinear at these doses. The pharmacokinetic differences betweenR-andS-thiopental, although small, were statistically significant and were influenced by the higher fu ofR-thiopental.