“Pharmacokinetics of Progesterone in Lactating Dairy Cows: Gaining some Insights into the Metabolism from Kinetic Modeling”

LUDMILA N. TURINO; RODOLFO N. MARIANO; MARÍA I. CABRERA; DANIEL E. SCÁNDOLO; MARTÍN G. MACIEL; RICARDO J.A. GRAU

JOURNAL OF DAIRY SCIENCE

The American Dairy Science Association

Lugar: Champaign, USA; Año: 2010 vol. 93 p. 988 - 999

0022-0302

The progesterone pharmacokinetics was analyzed for plasma hormone concentrations ranging from linear to saturated metabolism in lactating Holstein cows with differing daily milk yields. The adequacy of two-coupled first-order (bi-exponential equation), hyperbolic (Michaelis-Menten equation), and sigmoidal (Hill equation) kinetic models to describe the experimental progesterone pharmacokinetic profiles was examined on statistical basis. After non-linear regression and statistical analysis of the data fitting capability, a simple one-compartment model based on Hill equation proved to be most adequate. This model indicates an enzyme-catalyzed metabolism of progesterone involving co-operative substrate-binding sites, resulting from allosteric effects that yield a sigmoidal saturation rate curve. Kinetic parameters were estimated for two group of lactating Holstein cows with different daily milk yields. It was found, for the first time, a remarkable quantitative agreement of the Hill coefficient value with that reported in pharmacokinetic studies involving CYP3A mediated reactions in other mammals, humans included. It seems that positive co-operativity makes enzymes much more sensitive to plasma progesterone concentration and their activities can undergo significant changes in a narrow range of concentrations as characteristic of sigmoidal behavior. Therefore, the values of classical pharmacokinetic parameters, such as the elimination constant, half-life and clearance rate, were found to be highly dependent on the plasma progesterone concentration.