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

Abstract

Background: 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 of R- and S-thiopental and serum concentrations of R- and S-pentobarbital from prolonged high-dose infusion of thiopental for neuroprotection. Methods: Twenty patients received a mean thiopental dose of 41.2 g over a mean duration of 95 h. R- and S-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. Results: Nonlinear models were preferred in 16 of 18 patients. Paired analysis indicated that steady state clearance (C1(ss)) and volume of distribution (V(d)) were higher for R- thiopental (0.108 vs. 0.096 l/min, P < 0.0001; and 313 vs. 2731, P < 0.0005, respectively); maximal rate of metabolism (V(m)) was higher for S- than for R-thiopental (1.01 vs. 0.86 mg · 1-1 · 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, respectively, P < 0.0001). The differences in mean C1(ss), V(d) and V(m) were not significant when adjusted by f(u). Plasma concentrations of R- and S-pentobarbital 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 higher f(u) of R- thiopental.