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.

Comparison of luteolysis and timed artificial insemination pregnancy rates after administration of PGF2α in the muscle or the ischiorectal fossa in cattle

“…Therefore, the sample size of this study and analysis of the data was designed to detect a difference of 4 hours in time to luteolysis. While progesterone was not physically measured every 4 hours, fitting each progesterone curve with a sigmoidal logistic model (Turino et al, 2010) allowed for a more precise time to luteolysis to be estimated. No difference in time to luteolysis between treatment groups was found for each threshold examined.…”

“…Examples of serum progesterone curves for heifers that did not have a competent corpus luteum, heifers that did have a competent corpus luteum but did undergo luteolysis, and heifers that had a competent corpus luteum that did undergo luteolysis can be found in Appendix 1. For each heifer included in the analysis, a sigmoidal logistic model was used to predict when serum progesterone decreased to less than 1.5, 1.25, and 1 ng/mL (Turino et al, 2010). Reasoning for the use of multiple thesholds is explained in the discussion.…”

Colostrogenesis during an induced lactation in dairy cattle

“…The variation indicates that animals were at different stages of their ovulation cycle. The decline in P4 concentrations that occur during the P4 injections series (5–7 days) likely resulted increased metabolism that occurs by a positive cooperatively that makes metabolism enzymes (CYP2C & CPY3A) more sensitive to plasma progesterone concentration (Turino et al., ).…”

Metabolic level recognition of progesterone in dairy Holstein cows using probabilistic models

“…Turino et al (2010) have previously discussed this fact and suggested that it is caused not only by an increase in blood flow as a consequence of a greater DMI as it is usually reported (Sangsritavong et al, 2002), but also by a greater negative energy balance (NEBAL) associated with a major abundance of cP450 subunits. Additionally, it was proved that serum insulin concentration is reduced whereas NEBAL increased (Butler, 2000;2003), which concomitantly rises the relative abundance of hepatic Cyp2C and Cyp3A subunits (Lemley et al, 2008;2010).…”