The systemic and cerebral kinetics of thiopental in sheep: enantiomeric analysis.
Thiopental is used as a racemate (rac-thiopental). Enantiomeric pharmacokinetic differences could therefore influence the onset and duration of anesthesia of rac-thiopental. We studied the systemic and cerebral kinetics of R(+)- and S(-)-thiopental in five adult ewes after a 2-min intravenous infusion of 500 mg rac-thiopental sodium. Systemic kinetic values were determined from the time course of concentrations in arterial plasma; cerebral kinetic values were deduced from the time course of the concentration differences between arterial and superior sagittal sinus blood plasma. Enantiomeric differences were found in both sites, with the (R:S) ratio of thiopental enantiomer blood concentrations initially being > or = 1 then decreasing to < 1 after approximately 60 min. This is consistent with the finding of the mean total body clearance of R(+)-thiopental being 17% (SD 12%) greater than that of S(-)-thiopental (P = .04). Sagittal sinus plasma concentrations of both enantiomers followed closely behind those in arterial plasma and this is consistent with facile bidirectional exchange of thiopental between plasma and brain. No significant differences were found between enantiomers in the rates of brain influx or efflux. Onset and regression of anesthesia occurred while the enantiomer blood concentrations were similar. Hence published pharmacokinetic-pharmacodynamic models of the onset of thiopental effects probably are not significantly compromised by neglecting the enantiomeric duality of thiopental, but models based on its elimination kinetics could be compromised if enantiomeric differences are neglected.
Mather
L E
LE
Department of Anaesthesia and Pain Management, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW, Australia.
Upton
R N
RN
Huang
J L
JL
Ludbrook
G L
GL
Gray
E
E
Grant
C
C
D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D005260:Female; D008968:Molecular Conformation; D012756:Sheep; D013237:Stereoisomerism; D013874:Thiopental / Q000737:chemistry / Q000493:pharmacokinetics*
D018686:Anesthetics, Intravenous; D013874:Thiopental