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

• Published in: British journal of clinical pharmacology Vol. 43; no. 4; pp. 355 - 362
• Main Authors: Cordato, D. J., Gross, A. S., Herkes, G. K., Mather, L. E.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.04.1997; Blackwell Science; Blackwell Science Inc
• Subjects: Adult; Aged; Aged, 80 and over; Anesthesia; Anesthetics, Intravenous - administration & dosage; Anesthetics, Intravenous - blood; Anesthetics, Intravenous - cerebrospinal fluid; Anesthetics, Intravenous - chemistry; Anesthetics, Intravenous - pharmacokinetics; Anesthetics, Intravenous - therapeutic use; Anesthetics, Intravenous - urine; Anesthetics. Neuromuscular blocking agents; Biological and medical sciences; Blood Proteins - metabolism; Electroencephalography; enantiomers; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Medical sciences; Middle Aged; Neuropharmacology; Original; pharmacokinetics; Pharmacology. Drug treatments; Protein Binding - drug effects; Pseudotumor Cerebri - drug therapy; Stereoisomerism; Thiopental - administration & dosage; Thiopental - blood; Thiopental - cerebrospinal fluid; Thiopental - chemistry; Thiopental - pharmacokinetics; Thiopental - therapeutic use; Thiopental - urine; thiopentone; Human; Nervous system diseases; Thiopental sodium; Intravenous administration; Intracranial hypertension; Cerebral disorder; Chemotherapy; Bolus injection; Treatment; General anesthetic; Perfusion; Surgery; Enantiomer; Central nervous system disease; Barbiturates; Pharmacokinetics; Comparative study
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1046/j.1365-2125.1997.00567.x

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 V ss 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 V ss could be explained by enantioselective difference found in serum protein binding.