Mechanism-based inhibition, kinetic model

A number of reports also describe the prediction of mechanism-based inhibition (MBI) [17,18]. In this type of model, MBI is determined in part by spectral shift and inactivation kinetics. Jones et al. applied computational pharmacophores, recursive partitioning and logistic regression in attempts to predict metabolic intermediate complex (MIC) formation from structural inputs [17]. The development of models that accurately predict MIC formation will provide another tool to help reduce the overall risk of DDI [19]. 

It should be noted that the mechanism depicted in Scheme 1 is the simplest that is consistent with mechanism-based inhibition. The mechanism for a given inhibitor and enzyme may be considerably more complex due to (a) multiple intermediates [e.g., MIC formation often involves four or more intermediates (29)], (b) detectable metabolite that may be produced from more than one intermediate, and (c) the fact that enzyme-inhibitor complex may produce a metabolite that is mechanistically unrelated to the inactivation pathway. Events such as these will necessitate alternate definitions for Z inact, Kh and r in terms of the microrate constants of the appropriate model. The hyperbolic relationship between rate of inactivation and inhibitor concentration will, however, remain, unless nonhyperbolic kinetics characterize this interaction. Silverman discussed this possibility from the perspective of an allosteric interaction between inhibitor and enzyme (5). Nonhyperbolic kinetics has been observed for the interaction of several drugs with members of the CYPs (30). 

Kinetic model for mechanism-based inhibition is proposed in Scheme 16.3 (Waley, 1980 Walsh et al., 1978). Inactivation of the enzyme is an irreversible process over the time scale of the experiment. At the given concentrations of inhibitor and enzyme, the reactions indicated in Scheme 16.3 are governed by the first-order rate constants k, k, 2, k, and 4, respectively. The rate of enzyme inactivation can be introduced by Equation 16.3 (Jxmg and Metcalf, 1975 Kitz and Wilson, 1962). 

The kinetic model reproduces satisfectorily experimental results. Deactivation experiments seems to indicate that the mechanism of deactivation changes with the nature of the contaminant used. When a strong poison for active acidic sites like pyridine is used, the catalyst gets totally deactivated when its concentration is over 250 ppm. In this case, the deactivation is fester than with CS2, hut not as fest as an acid base reaction should be. The behavior can be explained assiuning that the pyridine reaction with acidic sites is a diffesion controlled phenomenon enhanced by its molecular size, which is very near to the zeolite pore size. The presence of a mixed mechanism of deactivation and inhibition is also evident. 

Power law model also provides good kinetic fit for the low-temperature WGS catalysts. Ovensen et al. [53] proposed microkinetic model based on surface redox mechanism and also evaluated the macroscopic power law kinetic model which was found to be an excellent representation of the kinetic data. Koryabkina et al. [54] determined the kinetic parameters for power law expression using catalysts based on copper over different supports. These authors suggested that there was a strong inhibition on the reaction rate by the products. They also proposed that the kinetics could be explained by a redox mechanism. The kinetic parameters obtained from different works are summarized in Table 9.5. 

Thus, the value analysis enables to structure chemically the prognosis. As a result new experiments can be planned that are described by constructing the kinetic models, to provide a more reliable prediction of the behavior of an inhibited reaction. For example, it can be recommended to study the reactions imder the conditions of lower initiation rates so that the pro-oxidant role of the inhibitor is unsuppressed. Or, alternatively, to plan experiments with the additions of hydrogen peroxide, hydroperoxide, quinolide peroxides that would reveal a wider set of steps in the base mechanism required to perform an adequate prognosis. However, as it follows from the results obtained at 120 and the reliable kinetic information about the initial reaction mechanism, the analysis of the inhibited reaction is evidently valid also for 60 °Cand37°C. 

The transient kinetic model of the standard SCR reaction over a commercial V-based catalyst for vehicles reported in Reference (101) is the only treatment available so far accounting both for the redox nature of the SCR catalytic mechanism and for the ammonia inhibition effect. It relies on a dual-site redox scheme, whereby ammonia is first adsorbed onto acidic sites, but reacts with NO on different redox sites associated with the vanadium component. The redox sites can, however, be blocked by excess ammonia. Adopting a Mars-Van Krevelen formal approach, the following modified redox (MR) rate expression was derived (27) ... 

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