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We present a mechanistic pharmacokinetic-pharmacodynamic model to simulate the effect of dexamethasone on the glucose metabolism in dairy cows.
The coupling of the pharmacokinetic model to the pharmacodynamic model
is based on mechanisms underlying homeostasis regulation by dexamethasone.
In particular, the coupling takes into account the predominant role of dexamethasone in stimulating glucagon secretion, glycogenolysis and lipolysis and in
impairing the sensitivity of cells to insulin. Simulating the effect of a single
dose of dexamethasone on the physiological behaviour of the system shows that
the adopted mechanisms are able to induce a temporary hyperglycemia and
hyperinsulinemia, which captures the observed data in non-lactating cows. In
lactating cows, the model simulations show that a single dose of dexamethasone
reduces the lipolytic effect, owing to the reduction of glucose uptake by the
mammary gland.
Nutrition plays a crucial role in regulating reproductive hormones and follicular
development in cattle. This is visible particularly during the time of negative
energy balance at the onset of milk production after calving. Here, elongated
periods of anovulation have been observed, resulting from alterations in luteiniz-
ing hormone concentrations, likely caused by lower glucose and insulin concen-
trations in the blood. The mechanisms that result in a reduced fertility are
not completely understood, although a close relationship to the glucose-insulin
metabolism is widely supported. Following this idea, a mathematical model of
the hormonal network combining reproductive hormones and hormones that are
coupled to the glucose compartments within the body of the cow was developed.
The model is built on ordinary differential equations and relies on previously
introduced models on the bovine estrous cycle and the glucose-insulin dynam-
ics. Necessary modifications and coupling mechanisms are thoroughly discussed.
Depending on the composition and the amount of food, in particular the glu-
cose content in the dry matter, the model quantifies reproductive hormones and
follicular development over time. Simulation results for different nutritional
regimes in lactating and non-lactating dairy cows are examined and compared
with experimental studies. Regarding its applicability, this work is an early
attempt towards developing in silico feeding strategies and may eventually help
refining and reducing animal experiments.