Kinetics kinetic profiles

FIGURE 8.23 Kinetic profiles of the plasma concentrations of three different drags taken by the oral route. If absorption is rapid, toxic effects may ensue (red line). If too slow, a therapeutically effective level may not be attained (blue line). 

Fig. 7.3.4 Kinetic profiles of the Diplocardia bioluminescence reaction, when Diplocardia luciferase, H2O2, or Diplocardia luciferin was injected last. In each case, 0.1 ml of the last component was injected into 0.9 ml of the mixture of other components, to give the final concentrations Diplocardia luciferase, 0.1 unit/ml Diplocardia luciferin, 32 mM and H2O2, 32 mM, in 0.1 M potassium phosphate buffer, pH 7.5. From Rudie et al., 1981, with permission from the American Chemical Society.

Most ACE inhibitors are prodrugs, with the exceptions of captopril, lisinopril, and ceranapril. Prodrugs exert improved oral bioavailability, but need to be converted to active compounds in the liver, kidney, and/or intestinal tract. In effect, converting enzyme inhibitors have quite different kinetic profiles with regard to half time, onset and duration of action, or tissue penetration. 

The different reactivity mentioned above also proves the validity of inequality ki, k3> >k4 used in the simplification of our model. On the contrary, in the presence of CHA less than one equivalent the signals of both the la and Ih appear, a large extent of deuteration at C-3 is observed both in the cis and tram isomers and in the product flavone (2). Using an excess of amine both isomer gave 2 deuterated at C-3 to an extent ca. 80-85 %. Considering the kinetic profile of the interconversion we conclude that it takes place via an enolate where the rate determining step is the deprotonation at C-3. 

FIGURE 4.2.3 UV-vis spectral changes and AAbs obtained by heating bixin in water ethanol (8 2) at 92°C. Inset shows kinetic profile at several wavelengths, with the solid lines representing the fitting of experimental data from the sum of two exponential functions. From Rios, A.O., Borsarelli, C.D., and Mercadante, A.Z., J. Agric. Food Chem., 53, 2307, 2005. With permission. 

FIG. 12 First-order kinetic profiles observed from CLM measurements of the diprotonation of H2TTP (a) and the demetalation of ZnTPP (b). The initial concentrations of H2TPP and ZnTPP were 1.71 x 10 and 8.9 x 10 moldm, respectively. The concentration of hydrochloric acid was 2.0moldm (Reprinted from Ref. 61. Cop5right 1998, American Chemical Society.)... 

Figure 27.1. Kinetic profiles for the coupling of 4-bromoanisole with phenylboronic acid to yield 4-bromonaphthalene, (a) using as-prepared BaCeo95Pdoo502 95 (open circles) or BaCeo9oPdoio02 9o (filled circles) as the catalyst and (b) using BaCeo95Pdoos02 95 as-prepared (small open circles) reduced (filled circles) and reoxidized (open squares) as the catalyst. Reagents and conditions 3.0 mg catalyst (0.05 mol % Pd, X = 0.05 0.10 mol % Pd, x = 0.10), 1.0 mmol 4-bromoanisole, 1.5 mmol PhB(OH)2, 4.0 mmol K2CO3, 12 mL IPA-H2O (1 1, v/v), 80°C. Lines are drawn only to guide the eye.

J. M. Hutzler, T. S. Tracy 2002, (Atypical kinetic profiles in drug metabolism reactions), Drug Metab. Dispos. 30(4), 355. 

The photobleaching of P-carotene by fluorescent light in fatty acid ester solutions showed an autoxidation kinetic profile with the rate of degradation of P-carotene in the order laurate > oleate > linoleate (Carnevale et al. 1979). The presence of a radical scavenger retarded the autoxidation, thus leading to the view that protection against autoxidation is built into the system by the unsaturation in the fatty acid. 

Three cyanide-degrading nitrilases were recently cloned and purified and their kinetic profiles were evaluated in order to better understand their applicability to cyanide bioremediation. CynD from Bacilluspumilus Cl and DyngD from Pseudomonas stutzeri exhibit fairly broad pH profiles with >50% activity retained across pH 5.2 to pH 8.0 while the CHT (NHase) from Gloeocercospora sorghi exhibited a more alkaline pH activity profile with almost all of its activity retained at pH 8.5, slightly lower thermal tolerance, and quite different metal tolerance compared with the two bacterial enzymes [46]. 

An enantioselective nitrilase from Pseudomonas putida isolated from soil cultured with 2 mM phenylacetonitrile was purified and characterized. This enzyme is comprised of 9-10 identical subunits each of 43 kDa. It exhibits a pH optimum at 7.0 and a temperature optimum at 40 °C (Ty2 = 160 min) and requires a reducing environment for activity. This nitrilase was shown to have an unusually high tolerance for acetone as co-solvent, with >50% activity retained in the presence of 30% acetone. The kinetic profile of this nitrilase reveals KM= 13.4mM, cat/ M = 0-9s 1mM 1 for mandelonitrile, ZfM = 3.6mM, kclJKM 5.2 s him-1 for phenylacetonitrile, and KM = 5.3 mM, kC lt/KM = 2.5 s 1 him 1 for indole 3-acetonitrile. Preliminary analysis of this enzyme with 5 mM mandelonitrile revealed formation of (/t)-mandelic acid with 99.9% ee [59]. 

Stephens, R. H., O Neill, C. A., Warhurst, A., Carlson, G. L., Rowiand, M., Warhurst, G., Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia, J. Pharmacol. Exp. Ther. 2001, 296, 584-591. 

In a study by Leitner of the iridium-catalyzed hydrogenation of imines, a nearly 20-fold increase in catalytic efficiency was observed due to a different kinetic profile in scC02 as compared to methylene chloride.358 The change in rate and selectivity found in scC02 with respect to the other solvents can be related to the following major points ... 

The time resolution of stopped flow experiments is typically 1-2 ms,21 and is determined by the time required to mix the solutions, flow the mixed solution to the detection chamber, and stop the flow. Smaller detection cells can be used to decrease the time resolution at the expense of the signal-to-noise ratio of the detected signals. Various kinetic traces have to be averaged to achieve good kinetic profiles and sample volumes of milliliters with concentrations of micromolar to millimolar are required. 

The three rate constants for Eq. (98) correspond to the acid-catalyzed, the acid-independent and the hydrolytic paths of the dimer-monomer equilibrium, respectively, and were evaluated independently (107). The results clearly demonstrate that the complexity of the kinetic processes is due to the interplay of the hydrolytic and the complex-formation steps and is not a consequence of electron transfer reactions. In fact, the first-order decomposition of the FeS03 complex is the only redox step which contributes to the overall kinetic profiles, because subsequent reactions with the sulfite ion radical and other intermediates are considerably faster. The presence of dioxygen did not affect the kinetic traces when a large excess of the metal ion is present, confirming that either the formation of the SO5 radical (Eq. (91)) is suppressed by reaction (101), or the reactions of Fe(II) with SO and HSO5 are preferred over those of HSO3 as was predicted by Warneck and Ziajka (86). Recently, first-order formation of iron(II) was confirmed in this system (108), which supports the first possibility cited, though the other alternative can also be feasible under certain circumstances. 

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. 

Kinetic profiles, fermentation, 11 29 Kinetic pumps, 21 54—56 types of, 21 63-70 Kinetic rates, 14 607 Kinetics. See also Adsorption kinetics batteries, 3 421-423 chemical vapor deposition, 5 810-812 colloids, 7 291-292... 

Relating the Time-Course of Plasma Concentrations to the Time-Course of Effect A critical decision to be made after the first human study is whether the compound s speed of onset and duration of action are likely to be consistent with the desired clinical response. Speed of onset is clearly of interest for treatments which are taken intermittently for symptoms rehef, for example, acute treatments for migraine, analgesics, or antihistamines for hay fever. Duration of action phase I is particularly important when the therapeutic effect needs to be sustained continuously, such as for anticonvulsants. The first information on the probable time course of action often comes from the plasma pharmacokinetic profile. However, it has become increasingly evident that the kinetic profile alone may be misleading, with the concentration-time and the effect-time curves being substantially different. Some reasons for this, with examples, include... 

An interesting aspect to CYP3A4-mediated drug oxidations is the susceptibility of the enzyme to exhibit a variety of atypical kinetic profiles including positive... 

The kinetic profiles displayed in Figure 3-32 have been integrated numerically with Matlab s stiff solver odel5s using the rate constants /ci=1000 M 1s 1, /c2=100 s 1 for the initial concentrations [A]o=l M, [Cat]o=10 4 M and [B]o=[C]o=0 M. For this model the standard Runge-Kutta routine is far too slow and thus useless. 

A paclitaxel fullerene derivative has been obtained by covalent linkage of the dmg to the C60 by means of an ester, the hydrolysis of which presents a favorable kinetic profile, with consequent release of paclitaxel (Zakharian et al., 2005). The in vitro tests show a good anticancer activity, holding out hope for enhancing the dmg efficacy... 

Nishino (1991) noted the presence of an induction period in the kinetic profile of reactions of solid wood samples with acetic anhydride vapour. The duration of this induction period decreased and the rate of reaction increased with both increasing temperature and concentration of acetic anhydride vapour in the reaction vessel (Nishino, 1991). The rate of reaction was diffusion limited, with the rate of diffusion being greatest in the longitudinal direction of the wood samples. This phenomenon is only found in solid wood samples, since no induction period was noted for the reaction of wood fibres with acetic anhydride vapour (Loras, 1968). 

A study of the reaction kinetics of the reaction of butyl isocyanate with wood has been performed (West and Banks, 1986 West and Banks, 1987). Reactions were performed without catalyst and using pyridine, triethylamine, 1,4-diazobicyclo [2,2,2-octane] or di-butyl-tin-diacetate as catalyst. The data showed that no catalyst was effective without the presence of a swelling solvent. Kinetic profiles were obtained, which were deconvo-luted to yield two component reaction curves. It was considered that these two curves represented reaction with lignin and the holocellulose component of the cell wall. 

Hill, C.A.S. and Hillier, J. (1999). Kinetic studies of the reaction of carboxylic acid anhydrides with wood. Experimental determination and modelling of kinetic profiles. Physical Chemistry and Chemical Physics, 1, 1569-1576. 

Zierer R. (1991). Prolonged infusion of Panax ginseng saponins into the rat does not alter the chemical and kinetic profile of hormones from the posterior pituitary. J Ethnopharmacol. 34(2-3) 269-74. 

Figure 7. HPLC kinetic profiles of reaction products of pectate lyases obtained from chromatofocused fractions of Erwinia chrysanthemi culture supernatants. Chromatofocused enzymes, eluted at pH 8.6 (A), pH 8.3 (B), pH 6.0 (C), and < pH 6.0 (D), were assayed under conditions similar to those described in Figure 5.

Detailed time-dependent NMR studies were also performed in order to evaluate the kinetic profile of the tandem reaction (Fig. 6.17). Experimental data was coherent with a reversibly-irreversihly-coupled model, suggesting the proposed rearrangement step to he faster compared to the iminolactone cycfizafion. The studies also revealed the forward nitroaldol formation to he of comparable rate to tandem cycfizafion, while the reverse nitroaldol reaction was slower and thereby rate determining for the overall DCR process. 

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