Excretion pharmacokinetic models

Absorption, distribution, biotransformation, and excretion of chemical compounds have been discussed as separate phenomena. In reality all these processes occur simultaneously, and are integrated processes, i.e., they all affect each other. In order to understand the movements of chemicals in the body, and for the delineation of the duration of action of a chemical m the organism, it is important to be able to quantify these toxicokinetic phases. For this purpose various models are used, of which the most widely utilized are the one-compartment, two-compartment, and various physiologically based pharmacokinetic models. These models resemble models used in ventilation engineering to characterize air exchange. 

Sato A, Nakajima T, Fujiwara Y, et al. 1977. A pharmacokinetic model to study the excretion of trichloroethylene and its metabolites after an inhalation exposure. Br J Ind Med 34 55-63. 

Fit the amount of 3,5,6-TCP excreted in individual urine samples to a one-compartment pharmacokinetic model that describes the time course of 3,5,6-TCP in urine of volunteers following the application of chlorpyrifos to the forearm (72% of dose excreted).3... 

Absorption, Distribution, Metabolism, and Excretion. Levels of cresols in blood were obtained from a single case report of a dermally exposed human (Green 1975). Data on the toxicokinetics of cresols in animals were contained in two acute oral studies that provided only limited quantitative information on the absorption, metabolism, and excretion of cresols (Bray et al. 1950 Williams 1938). A more complete oral toxicokinetics study, in addition to studies using dermal and inhalation exposure, would provide data that could be used to develop predictive pharmacokinetic models for cresols. Inclusion of several dose levels and exposure durations in these studies would provide a more complete picture of the toxicokinetics of cresols and allow a more accurate route by route comparison, because it would allow detection of saturation effects. Studies of the tissue distribution of cresols in the body might help identify possible target organs. 

Tuey DB, Matthews HB. 1980. Distribution and excretion of 2,2, 4,4, 5,5 -hexabromobiphenyl in rats and man Pharmacokinetic model predictions. Toxicol Appl Pharmacol 53 420-431. 

The rate of absorption of 2,k,5-T into the body appeared to be slower after external exposure than after oral administration in humans. Pharmacokinetic modeling indicated 91% of the 2,h,5-T absorbed through the skin would be cleared within 1 week. Measurement of 2,k,5-T excreted in urine of spray crews demonstrated that the maximum absorbed dose is not likely to exceed 0.1 mg per kg of body weight per work day. Urinary excretion provided a more reliable measure of dose than analysis of patches worn by the workers. Exposure was highest in mixers who handled the spray concentrate and in sprayers using backpack equipment. 

Chlorpyrifos Urinary TCP Use of pharmacokinetic modeling to estimate exposure dose from amount excreted in urine Appendix B... 

Comparative Toxicokinetics. Qualitatively, absorption, distribution, metabolism, and excretion appear to be similar in humans and laboratory animals. However, quantitative variations in the absorption, distribution, metabolism, and excretion of benzene have been observed with respect to exposure routes, sex, nutritional status, and species. Further studies that focus on these differences and their implications for human health would be useful. Additionally, in vitro studies using human tissue and further research into PBPK modeling in animals would contribute significantly to the understanding of the kinetics of benzene and would aid in the development of pharmacokinetic models of exposure in humans. These topics are being addressed in ongoing studies (see Section 2.10.3). 

Sontag (1986) Pharmacokinetic Model. An extended multicompartmental model (see Figure 2-9) describing the kinetic behavior of uranium (absorption, distribution, and excretion as a function of time) in the organs of male and female rats was developed using data taken from experiments performed on 13-month-old male and female Sprague-Dawley rats intravenously injected with 1.54 mCi/kg (57 kBq/kg) U-uranyl citrate and sacrificed at 7, 28, 84, 168, or 336 days after injection. 

The three major parameters examined in urinary excretion bioavailability studies are the cumulative amount of drug excreted unmetabolized in the urine ( Xu)-, the maximum urinary excretion rate (ERmax) and the time of maximum excretion rate (Tmax)- In simple pharmacokinetic models, the rate of appearance of drug in the urine is proportional to the concentration of drug in the systemic circulation. Thus, the values for Tmax and ERmax for urine studies are analogous to the Tmax and Cmax values derived from blood level studies. The value of r ax decreases as the absorption rate of the drug increases, and increases as the... 

Bioaccumulation can be estimated by a kinetic model. In kinetic models (sometimes called physiological models or physiologically based pharmacokinetic models), consideration is given to the dynamics of ingestion, internal transport, storage, metabolic transformation, and excretion processes that occur in each type of organism for each type of chemical. In kinetic models,... 

Fig. 3.2 Analogue computer-generated curves showing the levels (as fraction of the intravenous dose) of benzylpenicillin in the central (serum) and peripheral (tissue) compartments of the two-compartment pharmacokinetic model and the cumulative amount excreted unchanged in the urine as a function of time. The curves are based on the first-order rate constants (k12, k21, kel) associated with the compartmental pharmacokinetic model. Note...

Figure 10.1. Pharmacokinetic models for the excretion of iodipamide, iodoxamicacid, and ioglycam-ide in the dog (747-752).

In the later serum-gentamicin determinations, the elevation of measured serum-drug concentration over levels predicted by the pharmacokinetic model is most likely due to the inability of a one-compartment distribution model to properly describe the observed tissue sequestration of gentamicin and the later return of the drug from the tissues to the vascular compartment. This process would delay total drug excretion and cause an elevation of the later-time measurements of serum gentamicin concentration. 

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