AJP - Regulatory, Integrative and Comparative Physiology, Vol 243, Issue 1 7-17, Copyright © 1982 by American Physiological Society
Model of the kinetics of ketone bodies in humans
C. Cobelli, R. Nosadini, G. Toffolo, A. McCulloch, A. Avogaro, A. Tiengo and K. G. Alberti
The kinetics of ketone bodies was studied in normal humans by giving a
combined bolus intravenous injection of labeled acetoacetate ([14C]AcAc)
and D(--)-beta-hydroxybutyrate (beta-[14C]-OHB) to seven subjects after an
overnight fast, on two different occasions, and by collecting frequent
blood samples for 100 min. Kinetic data were analyzed with both
noncompartmental and compartmental modeling techniques. A four-compartment
model, representing AcAc and beta-OHB in blood and two equilibrating ketone
body compartments, inside the liver and extrahepatic tissues, was chosen as
the most reliable mathematical representation; it is physiologically
plausible and was able to accurately fit the data. The model permitted
evaluation of the in vivo rate of ketone body production in the liver, the
individual plasma clearance rates of AcAc and beta-OHB, their initial
volumes of distribution, and the transfer rate parameters among the four
ketone body compartments. Moreover, the model provided estimates of the
components of the rates of appearance of AcAc and beta-OHB in plasma due to
newly synthesized ketone body from acetyl-CoA in the liver, and to
interconversion and recycling in the liver and extrahepatic tissues. The
model also was used to evaluate other methodologies currently employed in
the analysis of ketone body turnover data: the conventional approach based
on use of the combined specific activity of AcAc and beta-OHB required
assumptions not satisfied in vivo, leading to substantial errors in key
parameter estimates.
