title: Pharmacokinetics of progesterone in lactating dairy cows: gaining some insights into the metabolism from kinetic modeling.
abstract: Progesterone pharmacokinetics were analyzed for plasma hormone concentrations ranging from linear to saturated metabolism in lactating Holstein cows with differing daily milk yields. The adequacy of 2-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 a statistical basis. After nonlinear 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 cooperative substrate-binding sites, resulting from allosteric effects that yield a sigmoidal saturation rate curve. Kinetic parameters were estimated for 2 groups of lactating Holstein cows with different daily milk yields. We found, for the first time, a remarkable quantitative agreement of the Hill coefficient value with that reported in pharmacokinetic studies involving cytochrome P450, family 3, subfamily A (CYP3A)-mediated reactions in other mammals, humans included. It seems that positive cooperativity makes enzymes much more sensitive to plasma progesterone concentration, and their activities can undergo significant changes in a narrow range of concentration 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.
authors.affiliation: Laboratorio de Química Fina, Instituto de Desarrollo Tecnológico para la Industria Química (INTEC), Universidad Nacional del Litoral, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Predio CCT-CONICET Santa Fe, Santa Fe, Argentina.
authors.forename: L N
authors.initials: LN
authors.lastname: Turino
authors.forename: R N
authors.initials: RN
authors.lastname: Mariano
authors.forename: M I
authors.initials: MI
authors.lastname: Cabrera
authors.forename: D E
authors.initials: DE
authors.lastname: Scándolo
authors.forename: M G
authors.initials: MG
authors.lastname: Maciel
authors.forename: R J A
authors.initials: RJ
authors.lastname: Grau
mesh_terms: D000818:Animals; D002417:Cattle / Q000378:metabolism*; D003612:Dairying; D005260:Female; D006207:Half-Life; D007774:Lactation / Q000502:physiology*; D008657:Metabolic Clearance Rate; D008892:Milk / Q000378:metabolism; D008954:Models, Biological; D011374:Progesterone / Q000097:blood / Q000493:pharmacokinetics*; D011372:Progestins / Q000493:pharmacokinetics*; D012044:Regression Analysis
chemical_list: D011372:Progestins; D011374:Progesterone