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Abstract
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).
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 µM).
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.
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 µM 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.