modelling using the SAAM/CONSAM pro-
gram (Berman and Weiss, 1978; Boston et
al., 1981).
We have conducted a series of
studies that propose that 3MH metabo-
lism in humans (Rathmacher et al., 1995),
cattle (Rathmacher et al., 1992a), dogs
(Rathmacher et al., 1993a), swine
(Rathmacher et al., 1996) and sheep
(Rathmacher et al., 1993c) can be defined
from a single bolus infusion of a stable
isotope, 3-[methyl-^2 H 3 ]methylhistidine.
Following the bolus dose of the stable
isotope tracer, serial blood samples and/or
urine were collected over 3–5 days. A
minimum of three exponentials were
required to describe the plasma decay
curve adequately. The kinetic linear-time-
invariant models of 3MH metabolism in
the whole animal were constructed by
using the SAAM/CONSAM modelling
program. Three different configurations of
a three-compartment model are described:
(i) a simple three-compartment model for
humans, cattle and dogs, in which plasma
kinetics (3-[methyl-^2 H 3 ]MH/3MH) are
described by compartment 1 and which
has one urinary exit from compartment 1;
(ii) a plasma–urinary kinetic three-com-
partment model with two exits for sheep (a
urinary exit out of compartment 1 and a
balenine exit out of tissue compartment 3);
and (iii) a plasma three-compartment
model with an exit out of tissue compart-
ment 3 in swine. The kinetic parameters
reflect the differences in the known physi-
ology of humans, cattle and dogs, com-
pared with sheep and swine that do not
quantitatively excrete 3MH into the urine.
Steady-state model calculations define
masses and fluxes of 3MH between the
three compartments, and importantly the
de novoproduction of 3MH. The de novo
production of 3MH for humans, cattle,
dogs, sheep and swine are 3.1, 6.0, 12.1,
10.3 and 7.2 μmol kg^1 day^1 , respectively.
Thede novoproduction of 3MH as
calculated by the compartmental model
was not different when compared with
3MH production as calculated via tradi-
tional urinary collection. Additionally, the
data suggest that steady-state compartment
masses and mass transfer rates may be
related to fat-free mass and muscle mass in
humans and swine, respectively.Species comparison of 3MH kinetics
Figures 2.9 and 2.10 and Tables 2.1 and 2.2
are a summary of the efforts to model 3MH
metabolism using a three-compartment
model in humans, cattle and dogs which
quantitatively excrete 3MH in urine, as
compared with sheep and swine which do
not. Figure 2.10 is a comparison of model
structures between the species. The
diversity of models between humans, cattle
and dogs, and sheep and swine reflects
differences in known physiology. In each
species, the tracer is injected into compart-
ment 1 which, based on the size (volume
and mass), is similar to plasma and extra-
cellular water space. Compartment 1 was
the sampling compartment and the com-
partment from which the steady-state
calculations were initiated. All models for
each species can be resolved by sampling
only plasma. The exception is sheep,
which, as shown in Fig. 2.10, required the
sampling of both plasma and urine.
However, the sheep model can be resolved
from the plasma kinetics of 3MH if the rate
of exit from compartment 1 is fixed. From
the steady-state calculations, the de novo
production of 3MH was obtained into com-
partment 3 for humans, cattle and dogs and
into compartment 2 for sheep and swine.
The de novoproduction of 3MH could be
placed as an entry into compartment 2 and
an identical rate calculated. The compart-
ment identity of compartments 2 and 3 is
intracellular pools of 3MH. The metabolic
form of 3MH in these compartments may
not be identical nor is the identity of com-
partments 2 or 3 for one species the same
for another species (i.e. cattle versus
sheep). The models also depict differences
in the route by which 3MH exits the
system. In humans, cattle and dogs, 3MH is
excreted quantitatively in the urine as
illustrated by the exit from compartment 1.
This urinary exit has been confirmed by
comparison of urinary excretion of 3MH
and model calculated values (Fig. 2.11).
Whereas sheep excrete only 15% of total38 J.A. Rathmacher