Clearance toxicokinetics

Data from both in vivo and in vitro systems showed PbTx-3 to have an intermediate extraction ratio, indicating in vivo clearance of PbTx-3 was equally dependent upon liver blood flow and the activity of toxin-metabolizing enzymes. Studies on the effects of varying flow rates and metabolism on the total body clearance of PbTx-3 are planned. Finally, comparison of in vivo metabolism data to those derived from in vitro metabolism in isolated perfused livers and isolated hepatocytes suggested that in vitro systems accurately reflect in vivo metabolic processes and can be used to predict the toxicokinetic parameters of PbTx-3. 

A large degree of variation is apparent in retention rates for americium in the liver among various animal species (Durbin 1973), as indicated by measured or estimated liver clearance half-times of approximately 5-16 days in rats, 152 days in baboons, 1-10 years in dogs, and 10 years in Chinese hamsters. A liver clearance half-time of 2 years has been estimated for humans (Griffith et al. 1983). Refer to Section 3.5.1 for information regarding toxicokinetic mechanisms that may play a role in interspecies differences in liver retention of americium. 

The primary endpoint of the toxicokinetic studies is the concentration-time prohle of the substance in plasma/blood and other biological fluids as well as in tissues. The excretion rate over time and the amount of metabolites in urine and bile are further possible primary endpoints of kinetic studies, sometimes providing information on the mass balance of the compound. From the primary data, clearance and half-life can be derived by several methods. From the excretion rate over time and from cumulative urinary excretion data and plasma/blood concentration measured during the sampling period, renal clearance can be calculated. The same is the case for the bUiary excretion. 

Renwick (1993) examined the relative magnitude of toxicokinetic and toxicodynamic variations between species in detail and found that toxicokinetic differences were generally greater than toxicodynamic differences. In order to allow for separate evaluations of differences in toxicokinetics and toxicodynamics, he proposed that the default interspecies UF of 10 should, by default, be subdivided into a sub-factor of 4 for toxicokinetics and a sub-factor of 2.5 for toxicodynamics. The suggested factor of 4 for differences in toxicokinetics was largely based on the extent of absorption and the rate of elimination or clearance in different experimental animals. The suggested... 

Walton et al. (2004) determined the extent of interspecies differences in the internal dose of compounds, which are eliminated primarily by renal excretion in humans. Renal excretion was also the main route of elimination in the test species for most of the compounds. Interspecies differences were apparent for both the mechanism of renal excretion (glomemlar filtration, tubular secretion, and/or reabsorption), and the extent of plasma protein binding. Both of these may affect renal clearance and therefore the magnitude of species differences in the internal dose. For compounds which were eliminated unchanged by both humans and the test species, the average difference in the internal dose between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats, and 13 for mice. This suggests that for renal excretion the differences between humans and the rat, and especially the mouse, may exceed the fourfold default factor for toxicokinetics. 

Estimation of this radiation dose is sometimes accomplished by modeling the sequence of events involved in the acquisition, deposition, clearance, and decay of radium within the body. While based on the current understanding of experimental data on radium toxicokinetics, different models make different assumptions about these processes, thereby resulting in different estimates of dose and risk. These models are described in numerous reports including BEIR IV (1988), ICRP (1979), and Raabe et al. (1983). In this section, the toxicokinetics of radium are described based on the available experimental data rather than on descriptions derived from models. 

The pharmacokinetic evaluation of biopharmaceuticals is generally simplified by the usual metabolism of products to small peptides and to amino acids, and thus classical biotransformation and metabolism studies are rarely necessary. Routine studies to assess mass balance are not useful. However, both single- and multiple-dose toxicokinetic data are essential in safety pharmacology asessments, and these can be complicated by two factors (1) biphasic clearance with a saturable, initial, receptor-dependent clearance phase, which may cause nonlinearity in dose-exposure relationships and doseresponses [14] and (2) antibody production against an antigenic biopharmaceutical that can alter clearance or activity in more chronic repeat-dose safety studies in the preclinical model. 

Figure 2.3 An example of a data-based toxicokinetic model, in this case a 1-compartment model. The concentration of chemical in an organism may increase by intake and uptake but decrease due to growth dilution, transformation or metabolism and elimination, excretion or clearance.

Reversed phase H P LC conditions have been used with good success in the analysis of low levels of specific alkaloids. For example, the toxicokinetics of methyllycaconitine were determined by analyzing mouse sera and tissue samples (kidney, brain, liver, muscle) with detection down to one part per billion using selected ion monitoring MS/MS conditions [66]. Similar procedures are being used to measure alkaloid clearance times in sheep sera for methyllycaconitine and deltaline (Gardner, unpublished data). 

Discussion of the empirical clearance rate and other toxicokinetic properties of the chemical. For example, does the concentration causing the effect vary significantly with duration or number of exposures ... 

Comparative Toxicokinetics. Available data Ifom ehronic rat inhalation bioassays show similar asbestos-induced respiratory effects to those in humans assoeiated with oeeupational exposure to asbestos (pulmonary fibrosis, lung cancer, and pleural mesothelioma), but the use of the rat data to predict human health risks from exposure to airborne asbestos has a number of areas of uneertainty, including those associated with interspecies differences in lifespan, airway morphometry, and breathing patterns. The development of rat and human lung retention models that incorporate species differences in anatomical and physiological parameters influencing deposition and clearance of asbestos fibers may decrease the... 

Toxicokinetic risk factors are those that can lead to increased Cmax (maximum concentration) and/or AUC (area under the curve of the concentration vs. time plot) of a given drug in a patient s liver. The drug in question can be the parent drug, its toxic metabolite, or a combination. The liver s increased exposure to drugs can be caused by increased drug absorption (e.g., for an orally administered medication) and/or decreased drug clearance. Some of the major causes of toxicokinetic risk factors are summarized next. 

From a practical viewpoint, human populations cannot be used to determine the rate of formation and clearance of markers and the influence of various factors on those rates. Therefore, most toxicokinetic studies are conducted in animal models. From detailed studies in animals, mathematical models are... 

Toxicokinetics Absorption of DCA is rapid from the intestinal tract into the bloodstream. Once in the bloodstream, DCA is distributed to the liver and muscles, and then in smaller quantities to the fat, kidney, and other tissues such as the brain and testes. The systemic clearance of DCA is significantly higher. The metabolism of DCA is mediated by a novel CST, CST-zeta found in cytosolic fraction. This enzyme appears to be subjected to autoinhibition by DCA. Although there are substantial species differences in the metabolism of DCA, autoinhibition seems to be true across the species including humans. The half-life of DCA in dogs and rats are between... 

Toxicokinetics TCA is readily absorbed from the gastrointestinal tract in experimental animals and humans and its clearance from blood is relatively slow relative to other HAAs. Approximately half of the administered dose was eliminated unchanged. There are substantial differences in the clearance by different species. Clearance is much faster in mice than in rats and human clearance is very slow. The half-life is 5.8 h in mice, 9.3 h in rats, 50 h in humans and approximately 200 h in dogs. TCA produces same metabolites as DCA with or without being converted to DCA. 

Most of the information on the toxicokinetics of dinitroanilines pertains to 2,4-dinitroaniline. Dinitroanilines are highly toxic to humans and are well absorbed from all routes of exposure. Nine metabolites were detected in rats administered [ C]2,4-dinitroaniline orally or intravenously. 2,4-Dinitrophenylhydroxylamine was the main metabolite and was excreted in the urine as the sulfate conjugate and in bile as the glucuronide. Amine hydroxylation and sulfation of 2,4-dinitroaniline are probable detoxification processes that occur rapidly and facilitate clearance. 

Toxicokinetics is a term used for describing kinetic studies conducted in conjunction with toxicology evaluations (Di Carlo 1982) that deal with absorption, distribution, and elimination processes of chemicals present at concentrations that produce toxic effects. By monitoring the blood concentrations of the chemical and/or metabolites over time after administration by different routes, the test chemical s bioavailability and kinetic characteristics can be readily obtained. The data also permit the determination of the so-called linear dose range based on area under the plasma versus time curve and clearance or other related toxicokinetic parameters, as well as the prediction of possible bioaccumulation after multiple doses. Changes in kinetic parameters after multiple exposures... 

---