Transport, transformation and distribution space of propofol in the rat liver studied by means of the indicator-dilution technique.
1. The transport, transformation and distribution space of the endovenous anaesthetic propofol in the isolated perfused rat liver were investigated by using the multiple-indicator dilution technique with constant infusion (step input). 2. The behaviour of propofol in the liver was described by a space-distributed variable transit-time model. The drug permeated the cell membrane at very high rates and its distribution into the cellular space was flow-limited. The apparent distribution space of propofol varied between 284 and 125 times the water space, and was inversely related to the tested portal concentrations (33-250 microM). 3. The corresponding ratios of intra- to extracellular concentration varied between 319 and 187, revealing a very high affinity of the liver for propofol. They most probably reflect binding to several cellular structures, including membranes and proteins. 3. The single-pass rate coefficients for biotransformation decreased with increases in the portal concentration of propofol. The liver released significant amounts of 4-hydroxypropofol, reaching 41.7 % of the total single pass of 67.2 microM propofol biotransformation. These results disprove previous notions that hydroxylation is rate limiting for conjugation and suggest that the liver might function as a 4-hydroxypropofol source for conjugation to glucuronic acid or sulfate in other tissues.
Department of Biochemistry, Laboratory of Liver Metabolism, University of Maringá, 87.020.900 Maringá, Brazil.
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D000465:Algorithms; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D001711:Biotransformation; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D007201:Indicator Dilution Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism*; D008954:Models, Biological; D015742:Propofol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D018686:Anesthetics, Intravenous; D015742:Propofol