Concentration ratio, inhibitors

The quantity and quality of experimental information determined by the new techniques call for the use of comprehensive data treatment and evaluation methods. In earlier literature, quite often kinetic studies were simplified by using pseudo-first-order conditions, the steady-state approach or initial rate methods. In some cases, these simplifications were fully justified but sometimes the approximations led to distorted results. Autoxidation reactions are particularly vulnerable to this problem because of strong kinetic coupling between the individual steps and feed-back reactions. It was demonstrated in many cases, that these reactions are very sensitive to the conditions applied and their kinetic profiles and stoichiometries may be significantly altered by changing the pH, the absolute concentrations and concentration ratios of the reactants, and also by the presence of trace amounts of impurities which may act either as catalysts and/or inhibitors. 

The FPL- or SAA-prepared coupons and panels were Immersed for 30 min In an aqueous (or aqueous/alcohollc) Inhibitor solution at room temperature, followed by rinsing In distilled, deionized water and forced air drying. Coverage levels of phosphonate and silane Inhibitors were determined by XPS from the surface concentration ratios of their characteristic elements, P/Al or Sl/Al, respectively. Selected organosllanes were applied to the metal surface by spraying, after dissolution (0.1 - 0.5%, v/v) In the EPON-Versamld primer formulation. 

Fig. 2. isozyme seiectivity of fluoroaiiyi amine monoamine oxidases (MAO) inhibitors. The seiectivity ratio was defined as the ratio of the concentrations of inhibitors required to decrease the activity of both forms of the enzyme at the same rate [77]. A high ratio thus indicates a B-seiective inhibitor. 

For experimental reasons (discussed below) the relative rate of decrease should be smaller than 0.01 sec."1. Since kA is of the order of 104 liter per mole per sec., [AH] must be of the order of 10 6 mole per liter. This low concentration of inhibitor will only have an appreciable effect on the rate of autoxidation if the rate of initiation—and consequently the rate of oxidation—is low. To measure the decrease in rate during the short-lived non-steady state, one must be able to determine these low velocities within short periods of time. From the usual inhibition formulas one can compute, for instance, that in order to obtain a ratio of original to inhibited rate of about 5 with [AH] = 10 6 mole per... 

If the concentration of inhibitors increases to such levels that the yeast metabolism is affected, the numerator in Eq. 6 will decrease. In case the ratio on the right-hand side of Eq. 6 decreases below a threshold value, no further increase in feed rate will be made. 

In the absence of catalysis, the inhibitor concentration and the ratio of k to k u the equilibrium association constant, will define the fraction of the enzyme bound with inhibitor at a given enzyme concentration. The enzyme-inhibitor complex proceeds to transform the inhibitor to an intermediate that may decompose to form a metabolite or react with the enzyme to form an inactive complex. First-order rate constants /o, /t , and kA determine the rates of these reactions and the concentration of intermediate at a given concentration of inhibitor and enzyme. 

The classic example of competitive inhibition is inhibition of succinate dehydrogenase, an enzyme, by the compound malonate. Hans Krebs first elucidated the details of the citric acid cycle by adding malonate to minced pigeon muscle tissue and observing which intermediates accumulated after incubation of the mixture with various substrates. The structure of malonate is very similar to that of succinate (see Figure 1). The enzyme will bind malonate but cannot act further on it. That is, the enzyme and inhibitor form a nonproductive complex. We call this competitive inhibition, as succinate and malonate appear to compete for the same site on the enzyme. With competitive inhibition, the percent of inhibition is a function of the ratio between inhibitor and substrate, not the absolute concentration of inhibitor. 

Fig. 12.2. The surface atom concentration ratio [Ce] to ([Ce] + [M]), in which M is either Al, Zn, or Fe, as a function of thickness of cerium oxide film, both determined by AES profiling, for alloys immersed in solution for the number of days indicated (from R.B.W. Hinton in Reviews on Corrosion Inhibitor Science and Technology (1993), edited by A. Raman and P. Labine, 1-10-1. Copyright by NACE International. All rights reserved by...

Conventional methods for establishing the existence of active transport are to analyze the effects of metabolic inhibitors, to correlate the rate of metabolism with the extent of ion flow or the concentration ratio between the inside concentration and the outside concentration of the cells, and to measure the current needed in a short-circuited system having identical compositions solution on each side. Measurements indicate that the flow contributing to the short-circuited current, and ary net flow detected are due to active transport, since the electrochemical gradients of all ions are zero (A // = 0, c0 = c,). 

From ESR spectra, the relative concentration of the radical products of reactions (99) and (100) was determined. When both reactions are sufficiently rapid, the concentration ratio is equal to k1/k2, i.e. to the relative reactivity of the monomer CH2=CHX with Me3CO radicals. In the same solvent, measurements with various monomers yield relative initiation rates [132] according to reaction (94). By a combination of this procedure with an absolute method (e.g. with inhibitors), for which the most favourable conditions can be selected, the accuracy of the determination of the kinetics and mechanism of initiation can be significantly enhanced. 

The most common type of inhibition is reversible inhibition. As the name implies, a reversible inhibitor functions by binding reversibly (generally noncovalently) to the target enzyme. An inhibitor forms a complex with the enzyme (an FT complex) the dissociation of that complex is measured by the K (the ratio of the rate of dissociation of the inhibitor to association of the inhibitor, kosikon, the concentration of inhibitor that gives half the maximal inhibition). As it is a dissociation constant, the smaller the Ki value for an inhibitor, the tighter the binding, and the more potent is the inhibitor. How these dissociation constants for the various types of inhibition are determined experimentally is described in the respective sections below. 

Studied [87-90]. -Butanol (BU) is an inhibitor of the Zn(II)/Zn(Hg) electrode process, whereas TU accelerates this process [87]. With the increase of TU concentration, the standard rate constant values increased to the maximum value of O.lcms , which is reached at the concentration of 0.33 M TU. When BU was added to TU solutions, the rate of the Zn(II)/Zn(Hg) process decreased. For the molar concentration ratio [BU]/[TU] 12,... 

Ritonavir (RTV) is also an inhibitor of HIV proteases, approved for use in combination with nucleoside analog, for the treatment of HIV-l infected adults, adolescents, and children. It is a potent CYP 3A4 inhibitor and is used at low doses to elevate plasma concentrations of other protease inhibitors being primarily metabolized by CYP 3A4. In combination with saquinavir, this type of interaction has proved favourable (28). The combination with nelfinavir showed much smaller effects on nelfinavir levels, but it appears to change in normal metabolizers the M8/nelfinavir concentration ratio from 0.3 to 0.6. In poor CYP 2C19 metaboliz-ers (-3-5% of Caucasians and African-Americans, -12-20% of Asians), ritonavir addition is not expected to have such an effect on the nelfinavir/M8 ratio (29). In addition, ritonavir induces CYP isoenzymes, so that the full effect of the nelfina-vir-ritonavir drug-drug interaction is considered stable after a treatment duration of 10-14 days (30). 

UDP-Glc is the most potent inhibitor of the animal UDP-Glc PPase. Thus, its concentration may have some regulation of the enzyme. The inhibition is competitive with UTP and it is suggested that the concentration ratio of UDP-Glc to UTP may be the most important determinant of UDP-Glc PPase activity. No other... 

As drugs are usually absorbed by passive diffusion and since enantiomers do not differ in their aqueous and lipid solubilities, absorption is not usually considered to be a stereoselective process. However, stereoselectivity has been described for drugs that are transported by a carrier-mediated process. Typical uptake selectivity is observed for neurotransmitter reuptake inhibitors such as nipecotic acid, oxaprotiline, fluoxetine and venlafaxine. Uptake of drugs by various organs can also be enantioselective, for example the liver/plasma concentration ratios of S(-) and R(-t-)-phenprocoumon in the rat were found to be different (6.9 and 5.2, respectively), indicating a preferential uptake of the more potent isomer. ... 

Since enzyme inhibition involves reversible mechanisms, CLi , (ij may vary with regard to the type and concentration of inhibitor. The concentrations of an inhibitor (or drug) that are relevant to clinical application can be approached for the prediction in the in vivo situation. In practice, a ratio in AUC, hepatic clearance (CLhept), plasma concentration at steady state (Css), or intrinsic clearance (CLjnt) caused by metabolism-based DDIs is commonly used to assess the degree of metabolism inhibition in vivo (Eq. 16.7). If a drug is eliminated due to both metabolism and renal excretion, the fraction of the drug metabolized by the inhibited enzyme (fj ) should be introduced to the prediction. With inclusion of fj, the ratio change in AUC in the presence and absence of an inhibitor can be expressed for competitive and noncompetitive (Eq. 16.8). 

The related agents paroxetine and sertraline (Fig. 11) contain two centers of chirality in their structures, but both are marketed as single stereoisomers. The latter agent is interesting because the stereochemistry of the molecule has a marked influence on the selectivity of drug action (Table 2). In the case of the irons isomers, the (- -)-enantiomer is a potent inhibitor of the uptake of serotonin, dopamine, and noradrenaline, the (—)-enantiomer being relatively selective for inhibition of noradrenaline uptake. In contrast, with the cis isomers, a separation of activity occurs with the (- -)-15,45-stereoisomer, sertraline, retaining potent serotonin uptake inhibition activity [87,88]. The selectivity of action, expressed as a concentration ratio for the inhibition of dopamine and noradrenaline... 

Rolipram is a racemic selective inhibitor of cAMP phosphodiesterase that has been used in the treatment of endogenous depression. The R(—)-enantiomer possesses the majority of the therapeutic eflect. After separate administration of the enantiomers by the oral and intravenous routes (Tables 1 and 2), no stereoselectivity appeared in plasma concentrations or in calculated pharmacokinetic [146]. However, it is not known whether this is also true after the administration of the racemate, because enantiomer-enantiomer interactions may affect the enantiomeric plasma concentration ratios of a number of chiral drugs. 

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