Electroencephalographic effects of thiopentone and its enantiomers in the rat: correlation with drug tissue distribution.
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.
Mather
L E
LE
Department of Anaesthesia and Pain Management, University of Sydney at Royal North Shore Hospital, St. Leonards, NSW 2065, Australia. lmather@med.usyd.edu.au
Edwards
S R
SR
Duke
C C
CC
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
D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; D013874:Thiopental