Metabolism coefficient

Insam H, Haselwandter K (1989) Metabolic coefficient of the soil microflora in relation to plant succession. Oecologia 79 174-178... 

Food metabolism and passage-rate studies using the inert tracer Cr have been conducted on the ring-necked pheasant (Phasianus colchicus) by G. E. Duke et al. (1968) wherein the Cr was applied to food. In single-dose studies, the CrCla solution was placed on a food pellet with a pipette. Excreta were counted with a scintillation counting system. Food consumption and total excreta data permitted computation of a metabolism coefficient ... 

The labeled foods enabled the investigators to associate excreta with specific foods assuming that the nuclide adheres tightly to a specific food in the gut. Continuous-dose studies utilized food that had been mixed uniformly with Cr and fed to test animals for one to several days. In these studies, the metabolism coefficient was equal to... 

The partition coefficient and aqueous solubility are properties important for the study of the adsorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) of drugs. The prediction of the ADME-Tox properties of drug candidates has recently attracted much interest because these properties account for the failure of about 60 % of all drug candidates in the clinical phases. The prediction of these properties in an early phase of the drug development process could therefore lead to significant savings in research and development costs. 

The respiratory quotient (RQ) is often used to estimate metabolic stoichiometry. Using quasi-steady-state and by definition of RQ, develop a system of two linear equations with two unknowns by solving a matrix under the following conditions the coefficient of the matrix with yeast growth (y = 4.14), ammonia (yN = 0) and glucose (ys = 4.0), where the evolution of C02 and biosynthesis are very small (o- = 0.095). Calculate the stoichiometric coefficient for RQ =1.0 for the above biological processes ... 

Table I summarizes some typical distribution coefficients. Sediments become enriched in plutonium with respect to water, usually with a factor of vlO5. Also living organisms enrich plutonium from natural waters, but usually less than sediments a factor of 103 - 101 is common. This indicates that the Kd-value for sediment (and soil) is probably governed by surface sorption phenomena. From the simplest organisms (plankton and plants) to man there is clear evidence of metabolic discrimination against transfer of plutonium. In general, the higher the species is on the trophic level, the smaller is the Kd-value. One may deduce from the Table that the concentration of plutonium accumulated in man in equilibrium with the environment, will not exceed the concentration of plutonium in the ground water, independent of the mode of ingestion.

In both intermediate and maximum rates of respiration, control is distributed between several different steps, including the activity of the adenine nucleotide translocator (Groen et al., 1983). It is now recognized that the idea of a simple rate-limiting step for a metabolic pathway is simplistic and that control is shared by all steps although to different extents (Kacserand Bums, 1978 Fell, 1992). Each step in a pathway has a flux control coefficient (FCC) defined as ... 

Physiologically Based Phamiacokinetic (PBPK) Model—Comprised of a series of compartments representing organs or tissue groups with realistic weights and blood flows. These models require a variety of physiological information tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates and, possibly membrane permeabilities. The models also utilize biochemical information such as air/blood partition coefficients, and metabolic parameters. PBPK models are also called biologically based tissue dosimetry models. 

As described above, some solutes such as gases can enter the cell by diffusing down an electrochemical gradient across the membrane and do not require metabolic energy. The simple passive diffusion of a solute across the membrane is limited by the thermal agitation of that specific molecule, by the concentration gradient across the membrane, and by the solubility of that solute (the permeability coefficient. Figure 41—6) in the hydrophobic core of the membrane bilayer. Solubility is... 

Some specific solutes diffuse down electrochemical gradients across membranes more rapidly than might be expected from their size, charge, or partition coefficients. This facilitated diffusion exhibits properties distinct from those of simple diffusion. The rate of facilitated diffusion, a uniport system, can be saturated ie, the number of sites involved in diffusion of the specific solutes appears finite. Many facihtated diffusion systems are stereospecific but, fike simple diffusion, require no metabolic energy. 

Metabolic control analysis (MCA) assigns a flux control coefficient (FCC) to each step in the pathway and considers the sum of the coefficients. Competing pathway components may have negative FCCs. To measure FCCs, a variety of experimental techniques including radio isotopomers and pulse chase experiments are necessary in a tissue culture system. Perturbation of the system, for example, with over-expression of various genes can be applied iteratively to understand and optimize product accumulation. 

Manners, C. N. Payling, D. W. Smith, D. A., Distribution coefficient, a convenient term for the relation of predictable physico-chemical properties to metabolic processes, Xenobiotica 18, 331-350 (1988). 

This book is written for the practicing pharmaceutical scientist involved in absorption-distribution-metabolism-excretion (ADME) measurements who needs to communicate with medicinal chemists persuasively, so that newly synthesized molecules will be more drug-like. ADME is all about a day in the life of a drug molecule (absorption, distribution, metabolism, and excretion). Specifically, this book attempts to describe the state of the art in measurement of ionization constants (p Ka), oil-water partition coefficients (log PI log D), solubility, and permeability (artificial phospholipid membrane barriers). Permeability is covered in considerable detail, based on a newly developed methodology known as parallel artificial membrane permeability assay (PAMPA). 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

The growth yield coefficients can be calculated [56,58] by sub-dividing metabolism responsible for the whole process of growth and multiplication into ... 

The yield coefficient of the poly(3HB) synthesis determined solely from carbon metabolism can easily be calculated if the metabolic sequence from the carbon substrate to poly(3HB) C4H602 is known, for instance ... 

A lowering of the permeability coefficients of compounds has been reported during the screening procedure using cell monolayers and commonly used excipients [98] (e.g., using PEG 400, DMSO), and it is also known that both DMSO and ethanol affect the general metabolic capacity of the cells, leading to an overestimation of permeability [156],... 

The genesis of in silico oral bioavailability predictions can be traced back to Lip-inski s Rule of Five and others qualitative attempts to describe drug-like molecules [13-15]. These processes are useful primarily as a qualitative tool in the early stage library design and in the candidate selection. Despite its large number of falsepositive results, Lipinski s Rule of Five has come into wide use as a qualitative tool to help the chemist design bioavailable compounds. It was concluded that compounds are most likely to have poor absorption when the molecular weight is >500, the calculated octan-l-ol/water partition coefficient (c log P) is >5, the number of H-bond donors is >5, and the number of H-bond acceptors is >10. Computation of these properties is now available as an ADME (absorption, distribution, metabolism, excretion) screen in commercial software such as Tsar (from Accelrys). The rule-of-5 should be seen as a qualitative, rather than quantitative, predictor of absorption and permeability [16, 17]. 

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