Pharmacokinetics of thiopentone enantiomers following intravenous injection or prolonged infusion of rac-thiopentone

摘要

Aims Thiopentone is administered as a racemate (rac-thiopentone) for induction of anaesthesia as well as for neurological and neurosurgical emergencies. The pharmacokinetics and pharmacodynamics of rac-thiopentone have been extensively studied but the component R-(+)- and S-(−)- enantiomers, until very recently, have been largely ignored.Methods The present study analyses the pharmacokinetics of R-(+)- and S-(−)-thiopentone in 12 patients given rac-thiopentone intravenously for induction of anaesthesia and five patients given a prolonged infusion of rac-thiopentone used for treatment of intracranial hypertension.Results The mean total body clearance (CLT ) and apparent volume of distribution at steady-state (V ss ) showed trends towards higher values for R-(+)- than for S-(−)-thiopentone in both patient groups; CLT and Vss of unbound fractions of R-(+)- and S-(−)-thiopentone, however, did not show these trends. The time courses of R-(+)- and S-(−)- thiopentone serum concentrations were so similar that EEG effect could not be attributed to one or other enantiomer. Serum protein binding for S-(−)-thiopentone was greater than for R-(+)-thiopentone (P=0.02) and 24 h urinary excretion of R-(+)-thiopentone was greater than for S-(−)thiopentone (P=0.03). In one patient, concomitant measurement of CSF and serum thiopentone concentrations found that serum: CSF equilibration of unbound fractions of both enantiomers was essentially complete.Conclusions The study was unable to determine any pharmacokinetic difference of clinical significance between the R-(+)- and S-(−)-thiopentone enantiomers and concludes that minor differences in CLT and Vss could be explained by enantioselective difference found in serum protein binding.