title: Electroencephalographic effects of thiopentone and its enantiomers in the rat: correlation with drug tissue distribution.
abstract: 1. To better understand the pharmacology of the thiopentone enantiomers, we studied their quantitative electroencephalographic effects and their distribution into vital tissues. 2. Adult Wistar rats were infused with rac-, R- or S-thiopentone at 4 mg kg(-1)min(-1) until death ensued. The EEG signal was acquired continuously; serial arterial plasma and terminal tissue thiopentone concentrations were measured enantiospecifically. Relevant drug tissue : plasma distribution coefficients and plasma concentration-EEG effect relationships were determined. 3. Doses (mg kg(-1)) (mean+/-s.e.mean) for anaesthesia (toe pinch) and lethality (respiratory failure), respectively, decreased in the order R-thiopentone (55.8+/-2.4 and 176.2+/-11.2)> rac-thiopentone (39.3+/-2.1 and 97.5+/-3.9)> S-thiopentone (35.6+/-1.9 and 74.2+/-5.2); plasma drug concentrations (microg ml(-1)) decreased in the order R-thiopentone (66.3+/-4.5 and 89.8+/-5.2)> rac-thiopentone (56.7+/-2.0 and 77. 8+/-2.8)> S-thiopentone (55.0+/-1.9 and 64.1+/-2.8). 4. Initial EEG activation was similar for all thiopentone forms. Plasma drug concentrations for the same extent of EEG deactivation reflected the potency order. 5. After infusion of rac-thiopentone, tissue : plasma distribution coefficients were higher for R- than for S-thiopentone in brain and visceral regions, but not in fat or muscle. After infusion of the separate enantiomers, the relative heart : brain distribution ratio was for S-thiopentone was double that for R-thiopentone. 6. The therapeutic index of R-thiopentone (3.16+/-0. 14) was more advantageous than either rac-thiopentone (2.52+/-0.13) or S-thiopentone (2.10+/-0.14), possibly due to the relatively greater distribution into CNS tissues than heart. The data suggest that R-thiopentone could make a satisfactory single enantiomer substitute for rac-thiopentone.
authors.affiliation: Department of Anaesthesia and Pain Management, University of Sydney at Royal North Shore Hospital, St. Leonards, NSW 2065, Australia. lmather@med.usyd.edu.au
authors.forename: L E
authors.initials: LE
authors.lastname: Mather
authors.forename: S R
authors.initials: SR
authors.lastname: Edwards
authors.forename: C C
authors.initials: CC
authors.lastname: Duke
mesh_terms: D018686:Anesthetics, Intravenous / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects*; D006993:Hypnotics and Sedatives / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013874:Thiopental / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; D013874:Thiopental