Threshold pharmacokinetic

In distributed pharmacokinetics, threshold models, in which a biological response is associated with the increase of concentration above a threshold value, are likewise dependent on spatial location. 

A toxicant must be present at its cellular site of action in sufficient amounts to exert its deleterious effects. When the concentration is too small it is said that the threshold has not been reached therefore, the material does not exert any adverse action. The distribution of active substances in the body is not uniform, and certain cells can exhibit preferentially high affinities for particular agents. Pharmacokinetic thresholds determine the effective dose of a chemical at its biological target site based on the absorption, distribution, biotransformation, and excretion of the particular chemical. 

The transition from linear to nonlinear kinetics as the dose level increases constitutes the pharmacokinetic threshold. Since the biological process represented by a pharmacokinetic model comprise a continuum of events, the pharmacokinetic threshold must be considered a gradual transition from linear to nonlinear kinetics with increasing dose level. Rather than a single precisely defined dose level, the threshold is a range of dose levels over which this transition occurs. However, the exact dose range at which deviation from kinetic linearity becomes apparent is relatively unimportant. The major concern is whether extrapolations are made from toxicity data obtained at dose levels either above or below the pharmacokinetic threshold transition. 

Hypothetical Illustration. Since observations of carcinogenic response arise from chronic (i.e., long term) studies, it will be appropriate to illustrate the existence of a pharmacokinetic threshold based on changes in the steady state level of a parent chemical and one of its metabolites at successively increasing dose levels. We will then investigate the cases where either the parent chemical or its metabolite is the carcinogenic entity. 

The hypothetical model chosen to illustrate the pharmacokinetic threshold is presented in Figure 2. The input of chemical is considered to occur at an uninterrupted constant rate (k°) as might be the case for continuous environmental exposure, and this input rate is the dose level under investigation. The parent chemical P can be excreted by a first order process kp or metabolized to metabolite M by the saturable process characterized by VjQp and Kmp. The metabolite can also be excreted by a... 

Similar results for the case in which the metabolite M is the carcinogenic entity are shown in Table II. In this case the predicted response may be either under-estimated or over-estimated when it is based on the observed response at dose levels exceeding the pharmacokinetic threshold. However, as is the case with the parent chemical, dose levels below the pharmacokinetic threshold are proportional to the concentration of the metabolite in the body, and can be used to predict the response at even lower levels. 

In both of the foregoing examples, the consistent (linear) relationship between the concentration of the carcinogenic entity and the dose level below the pharmacokinetic threshold yields consistent estimates for the parameter 3 over this dose range. However inconsistent estimates of 3 derived from dose levels above the pharmacokinetic threshold arise from the nonlinear relationship between the concentration of the entity inducing the carcinogenic response and the dose level. 

The foregoing simulation illustrates the inadequacy of dose response data obtained at dose levels above the pharmacokinetic threshold to predict the response at lower dose levels when the prediction is based on dose levels alone. It should be emphasized that the magnitude of the error in the predicted response in this example (pointed out by the ratios in Tables I and II) is of little quantitative significance. The magnitude of the error may change by many fold depending on the parameters of the model employed. It is far more important that the errors in estimated response are in direct proportion to the extent that the relationship between the steady state level of the carcinogenic entity and the dose level deviates from the linear relationship maintained at levels below the pharmacokinetic threshold. 

The pharmacokinetic threshold has significance far beyond the specialized endeavor of carcinogenic risk estimation. Since virtually any toxic response is a function of the concentration X time product of the toxic chemical in the sensitive tissue, the relationship between steady state concentrations and administered dose levels is crucial in interpreting and predicting any toxic response as a function of exposure level. In particular, when otherwise efficient defense mechanisms or detoxification pathways are overwhelmed at sufficiently high dose levels dramatic nonlinear increases in toxicity may arise (, ). ... 

However, Gehring et al. were able to utilize dose response data obtained above the pharmacokinetic threshold by determining the pharmacokinetic parameters describing the saturable metabolism of inhaled VC in rats (S), With knowledge of the Vm and values for the metabolic transformation of VC in rats, it was possible to index the observed response to the internal dose level of the toxic entity (the amount of VC metabolized), rather than to the exposure level. 

Within this context, the range of dose levels of a chemical causing a transition from a linear to a nonlinear pharmacokinetic profile comprise the pharmacokinetic threshold dose range for the chemical. The change in the relationship between the internal concentration of the toxic entity and the dose level must be taken into account when extrapolating the observed response at dose levels above the pharmacokinetic threshold to the expected response at much lower dose levels. 

Exposure should be by the practical route. Other conditions, such as number and magnitude of exposures, should kiclude at least one level representative of the practical situation monitoring should be appropriate to the needs for conducting the study and when practically and economically possible, pharmacokinetic observations should be undertaken ki order to better define the relationship of dose to metaboHc thresholds. 

Pharmacokinetics. Figure 2 Sigmoid Emax model of pharmacodynamics with Hill coefficient (H), concentration producing half-maximum effect (CE50), threshold concentration (CE05), and ceiling concentration (CE95). 

Tse, F.L.S. and Jaffe, J.M. (1991). Preclinical Drug Disposition. Marcel Dekker, New York. Vinegar, A. and Jepson, G. (1996). Cardiac sensitization thresholds of halon replacement chemicals in humans by physiologically based pharmacokinetic modeling. Risk Analysis 16 571-579. 

A simple example might make this clearer. Suppose it were known that a 100 mg dose of chemical Z produced an extra 10% incidence of liver tumors in rats. Suppose further that we studied the pharmacokinetics of compound Z and discovered that, at the same 100 mg dose, 10 mg of the carcinogenic metabolite of Z was present in the liver. The usual regulatory default would instruct us to select the 100 mg dose as the point-of-departure for low dose extrapolation, and to draw a straight line to the origin, as in Figure 8.1. We are then further instructed to estimate the upper bound on risk at whatever dose humans are exposed to - let us say 1 mg. If the extra risk is 10% at 100 mg, then under the simple linear no-threshold model the extra risk at 1 mg should be 10% 100 = 0.1% (an extra risk of... 

Mecfianism of Action A methylxanthine and competitive inhibitor of phosphodiesterase that blocks antagonism of adenosine receptors. Therapeutic Effect Stimulates respiratory center, increases minute ventilation, decreases threshold of or increases response to hypercapnia, increases skeletal muscle tone, decreases diaphragmatic fatigue, increases metabolic rate, and increases oxygen consumption. Pharmacokinetics Protein binding 36%. Widely distributed through the tissues and CSF. Metabolized in liver. Excreted in urine. Half-life 3-7 hr. 

Mechanism of Action An opioid agonist that binds to opioid receptors in the CNS, reducing stimuli from sensory nerve endings and inhibiting ascending pain pathways. Therapeutic Effect Alters pain reception and increases the pain threshold. Pharmacokinetics ... 

Chemical clastogenesis and mutagenesis both involve a complex series of processes, including pharmacokinetic mechanisms (uptake, transport, diffusion, excretion), metabolic activation and inactivation, production of DNA lesions and their incomplete repair or misrepair, and steps leading to the subsequent expression of mutations in surviving cells or individuals (Thble 7.1). Each of the steps in these processes might conceivably involve first order kinetics at low doses (e.g., diffusion, MichaeUs-Menten enzyme kinetics) and hence be linear. In principle, therefore, the overall process edso might be linear and without threshold. 

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