Steady-state propofol brain:plasma and brain:blood partition coefficients and the effect-site equilibration paradox.
Based on volume-flow relationships, CNS agents that are highly lipid soluble (log octanol-water partition coefficient > 2) are expected to have equilibration half-times (T1/2 kE0) that are proportional to brain solubility. Propofol, the most lipophilic anaesthetic in clinical use, has T1/2 kE0 values of 1.7 and 2.9 min in rats and humans, respectively, compared with an expected value of at least 8 min. As a first step in exploring this discrepancy between observed and predicted values, we determined the steady state brain:plasma and brain:blood partition coefficients in rats after a 4-h infusion of propofol. Brain:plasma and brain:blood partition coefficients were 8.2 (SD 1.6) and 3.0 (0.5), respectively. T1/2 kE0 predictions based on brain: blood partitioning in rats are more in agreement with the observed equilibration half-time, suggesting that drug bound to the formed elements of blood participates in the uptake and transfer of propofol to its effect site.
Dutta
S
S
Department of Pharmaceutics, State University of New York at Buffalo, Amherst 14260, USA.
Matsumoto
Y
Y
Muramatsu
A
A
Matsumoto
M
M
Fukuoka
M
M
Ebling
W F
WF
D000704:Analysis of Variance; D018686:Anesthetics, Intravenous / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D015742:Propofol / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility
D018686:Anesthetics, Intravenous; D015742:Propofol