Pharmacokinetics of thiopentone enantiomers following intravenous injection or prolonged infusion of rac-thiopentone.
OBJECTIVE
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 (Vss) 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.
Cordato
D J
DJ
Department of Neurology, Royal North Shore Hospital, Sydney, Australia.
Gross
A S
AS
Herkes
G K
GK
Mather
L E
LE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000758:Anesthesia; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D001798:Blood Proteins / Q000378:metabolism; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D011485:Protein Binding / Q000187:drug effects; D011559:Pseudotumor Cerebri / Q000188:drug therapy*; D013237:Stereoisomerism; D013874:Thiopental / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine
D018686:Anesthetics, Intravenous; D001798:Blood Proteins; D013874:Thiopental