Metabolic rate constant

Thus, the overall elimination rate constant (ke[) here is the sum of the urinary excretion rate constant (ke) and the metabolism rate constant (km) ... 

R Brown, H Seifried. Extrapolation of in vivo metabolic rate constants from in vitro pharmacokinetic data. Washington, DC US Environmental Protection Agency, 1988. 

Portmann and co-workers then studied the kinetic pathways in man for hydroxynalidixic acid, the active primary metabolite.(26) The rate constants for glucuronide formation, oxidation to the dicarboxylic acid and excretion of hydroxynalidixic acid were calculated. Essentially total absorption of hydroxynalidixic acid was found in every case. Good agreement between experimental and theoretical plasma levels, based on the first order rate approximations used for the model, was found. Again, the disappearance rate constant, kdoi was found to be very similar for each subject, although the individual excretion and metabolic rate constants varied widely. The disappearance rate constant, k was defined as the sum of the excretion rate constant, kg j and the metabolic rate constants to the glucuronide and dicarboxylic acid, kM-j and kgj, respectively. 

These in vivo and in vitro human metabolism studies indicate that pyrethroids undergo rapid metabolism and elimination as observed in rats, and qualitative metabolic profiles (e.g., kinds of metabolites) of pyrethroids are assumed to be almost the same between humans and rats, suggesting that a large database of animal metabolism of pyrethroids could provide useful information for the evaluation of behavior of pyrethroids in humans. Nowadays, human pesticide dosing studies for regulatory propose are severely restricted in the US, and thus detailed comparison of in vitro metabolism (e.g., metabolic rate constants of pathways on a step-by-step basis) using human and animal tissues could be an appropriate method to confirm the similarity or differences in metabolism between humans and animals. 

In chemical-specific parameters used for PBPK modeling, the metabolic rate constant is crucial to the accuracy of modeling results in many cases. For some pyrethroids, hydrolysis in intestine and serum has a significant role in the metabolism of the compound in mammals besides oxidation and ester cleavage in liver, which is the most important organ for detoxification of many chemicals. 

Fig. 6 Seven-compartment PBPK model for deltamethrin Km represents metabolic rate constant (Kml carboxylesterase in blood, Km2 cytochrome P450 in liver, Km3 carboxylesterase in liver, KmFcc rate constant in feces) [49]...

The metabolism of chloroform is well understood. Approximately 50% of an oral dose of 0.5 grams of chloroform was metabolized to carbon dioxide in humans (Fry et al. 1972). Metabolism was dose-dependent, decreasing with higher exposure. A first-pass effect was observed after oral exposure (Chiou 1975). Approximately 38% of the dose was converted in the liver, and < 17% was exhaled unchanged from the lungs before reaching the systemic circulation. On the basis of pharmacokinetic results obtained in rats and mice exposed to chloroform by inhalation, and of enzymatic studies in human tissues in vitro, in vivo metabolic rate constants (V, 3,C =15.7 mg/hour/kg, = 0.448 mg/L) were defined for humans (Corley et al. 1990). The metabolic activation of chloroform to its toxic intermediate, phosgene, was slower in humans than in rodents. 

Validation of the Model. The Corley model was validated using chloroform data sets from oral (Brown et al. 1974a) and intraperitoneal (Ilett et al. 1973) routes of administration and from human pharmacokinetic studies (Fry et al. 1972). Metabolic rate constants obtained from the gas-uptake experiments were validated by modeling the disposition of radiolabeled chloroform in mice and rats following inhalation of chloroform at much lower doses. For the oral data set, the model accurately predicted the total amounts of chloroform metabolized for both rats and mice. 

The classical compartmental and more complex PBPK models require actual pharmacokinetic data to calibrate some parameters such as metabolic rate constants. However, PBPK models are more data-intensive and require greater numbers of chemical-specific and receptor-specific inputs. Although PBPK models have been used extensively in the last 20 years to address cross-species differences and other uncertainties, there are cases in which simpler one- or two-compartment models have been sufficient for risk assessment, for example for methyl mercury (EPA 2001). 

First-order metabolic rate constant (per hour per kg liver) 3.25 1.75 2 — 1.65... 

Metabolic rate constants and absorption rate constants were estimated using data for excretion of... 

If during the experiment, the fish are growing and the chemical is metabolized, the specific growth rate constant (kg) and the metabolism rate constant (kup) must be included in Eq. (3) ... 

Reaction rate parameters required for the distributed pharmacokinetic model generally come from independent experimental data. One source is the analysis of rates of metabolism of cells grown in culture. However, the parameters from this source are potentially subject to considerable artifact, since cofactors and cellular interactions may be absent in vitro that are present in vivo. Published enzyme activities are a second source, but these are even more subject to artifact. A third source is previous compartmental analysis of a tissue dosed uniformly by intravenous infusion. If a compartment in such a study can be closely identified with the organ or tissue later considered in distributed pharmacokinetic analysis, then its compartmental clearance constant can often be used to derive the required metabolic rate constant. 

Gargas, M.L. and Seybold, P.G. (1988). Modeling the Tissue Solubilities and Metabolic Rate Constant (Vmax) of Halogenated Methanes, Ethanes, and Ethylenes. Toxicol.Lett., 43, 235-256. 

Whereas compartmental models are abstract mathematical representations of an animal or a human body, in the form of a certain number of boxes, PBPK models describe the behavior of xenobiotics on the basis of the actual anatomy, physiology, and biochemistry of human beings and animals. Being realistically modeled on how the body functions, PBPK models take into consideration the complex relationships that exist between critical biological and physicochemical determinants such as blood flow, ventilation rates, metabolic rate constants, tissue solubilities, and binding to proteins (e.g., albumin and glycoproteins) or other macromolecules (e.g., DNA and hemoglobin). 

Kim C, Manning RO, Brown RP, Bruckner JV. Use of the vial equilibration technique for determination of metabolic rate constants for dichloromethane. Toxicol Appl Pharmacol 1996 139 243-51. 

Kedderis, GM. In vitro to in vivo extrapolation of metabolic rate constants for physiologically based pharmacokinetic models. In JC Lipscomb and EV Ohanian, editors Toxicokinetics and Risk Assessment. Informa Healthcare Publishers, New York, 2007. 

Partition coefficients Metabolic rate constants Elimination rate constants Molecular weight Aqueous solubility Vapor pressure Permeability coefficients Diffusion coefficients Protein-binding constants... 

Gargas ML, Seybold PG, Andersen ME. 1988. Modeling the tissue solubilities and metabolic rate constant (Vmax) of halogenated methanes, ethanes and ethylenes. Toxicol Lett 43 235-256. 

Metabolism Rate Constant (k) from the Physiologic Model... 

We can apply kinetic principles to the phenomenon of bioconcentration. It is possible to describe the uptake (rate constant k ), clearance (also called depuration, rate constant fci), and metabolism (rate constant k, ) of non-polar pollutants into organisms such as fish by means of kinetic equations. Analysis of the dependence of the concentration of the toxic substance with time is called toxicokinetics... 

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