Rate processes 10-13 physiological responses

An instructive example is the physiological variable serum creatinine. Creatinine is an endogenous metabolite formed from, and thus reflecting, muscle mass. Total body muscle mass is sufficiently constant to render measurement of serum creatinine useful for assessing actual renal function. The serum value of creatinine (R) is namely dependent on the continuous (zero-order) input of creatinine into the blood (A in) and its renal elimination rate, which is a first-order rate process (A out x ) In case of an extensive muscle breakdown, kin will temporarily increase. It may also be permanently low, for example in old age when muscle mass is reduced. Likewise, creatinine clearance may decrease for various reasons, described by a decrease in A out- An increase in creatinine clearance may occur as well, for example following recovery from renal disease. According to pharmacodynamic indirect response models. 

From this point of view, the obvious issues that need addressing are those of the achievement of the equilibrium or pseudoequilibrium condition (i.e. the critical chemical kinetics in the medium), of the nature and rate of the slow step in the chain of processes that link the principal metal species to the physiological response (i.e. the actual physiological mechanism of metal action) and, of course, the environmental meaning of it all. 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

Physiological responses and, in particular, the catecholamines and their concomitant impacts on other physiological functions, such as blood pressure, heart rate, and lipolysis, may serve as objective indicators of the stress process. However, these bodily responses are also assumed to link psychosocial stress to increased health risks. 

In general there is a set of criteria which can be used to demonstrate whether an observed step is, or can be, on the direct pathway of a complex process. The rate of the step and its dependence on changing conditions has to be compatible with the overall rate. It is of course easier to exclude a step from the direct pathway, because it is too slow, than it is to ascertain its inclusion. This applies in the exploration of enzyme reactions, as will be discussed in detail in section 5.1, as well as to physiological responses. An example of the latter, which will be used to illustrate points in different sections, is the relation between steps in the hydrolysis of ATP by myosin and structural and mechanical changes during muscle contraction. Similarly the time course of calcium release and removal has to be correlated with the stimulation and relaxation of contraction and other phenomena. 

In many sequential processes, the overall rate of a pathway is determined by the rate of the slowest individual reaction. This is called the rate determining step (RDS) or rate limiting step (RLS).Thus if the rate of an early enzyme catalysed reaction is regulated (increased or decreased) in response to physiological conditions, then the overall rate of the pathway and substrate utilization will be subject to control. 

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