Physiological distribution

Physiologically based PK studies take a different perspective in modeling drug disposition in human body — a mechanistic physiologic distribution model. This approach had been in use in other disciplines long before the compartment kinetic modeling was applied for... 

The first processes we consider are environmental production and distribution, and the probable modes of human exposure. Then we consider the distribution to tissues even though this area of inquiry, pharmacokinetics, has not yet had a tremendous impact on deciding whether or not a chemical represents a public health hazard, models of physiological distribution are important in understanding toxicology in humans. 

After oral administration it is absorbed in the small intestine and undergoes rapid metabolism to 1,25 (OH)2 D3 in liver and further distribution to bone and intestine is nearly similar to its physiological distribution. 

Von Willebrand factor is the adhesive protein with an essential role in promoting interactions between platelets and vascular subendothelium. VWF is synthesized by endothelial cells and megakaryocytes. Endothelial cells release their synthesized VWF to the plasma and the vessel subendothelium, while the VWF produced by megakaryoc34es is stored in the platelet alpha granules [20]. VWF is thus physiologically distributed in plasma, subendothelium and platelets. Adequate hemostasis requires balanced interactions among the VWF located in these three compartments. 

Physiological Distribution of Atropine In the Rat. Pharmacol. Blochem. Behav. 2 843-845 ... 

Migula, P., Nuorteva, P., Nuorteva, S.-L., Glowacka, E., Oja, A., 1993. Physiological distribution in ants Formica aquilonia) from excess of cadmium and mercury in Finnish forest. Sci. Total Environ. (Suppl.), 1305-1314. 

Histamine in the Cardiovascular System. It has been known for many years that histamine is present in sympathetic nerves and has a distribution within the heart that parallels that of norepinephrine (see Epinephrine and norepinephrine). A physiological role for cardiac histamine as a modulator of sympathetic responses is highly plausible (15). A pool of histamine in rat heart located neither in mast cells nor in sympathetic nerves has been demonstrated. The turnover of this metaboHcaHy active pool of histamine appears to be maintained by normal sympathetic activity. 

Pharmacodynamics is the study of dmg action primarily in terms of dmg stmcture, site of action, and the biochemical and physiological consequences of the dmg action. The availabiUty of a dmg at its site of action is deterrnined by several processes (Fig. 1), including absorption, metaboHsm, distribution, and excretion. These processes constitute the pharmacokinetic aspects of dmg action. The onset, intensity, and duration of dmg action are deterrnined by these factors as well as by the avadabihty of the dmg at its receptor site(s) and the events initiated by receptor activation (see Drug delivery). 

Dmg distribution into tissue reservoirs depends on the physicochemical properties of the dmg. Tissue reservoirs include fat, bone, and the principal body organs. Access of dmgs to these reservoirs depends on partition coefficient, charge or degree of ionization at physiological pH, and extent of protein binding. Thus, lipophilic molecules accumulate in fat reservoirs and this accumulation can alter considerably both the duration and the concentration—response curves of dmg action. Some dmgs may accumulate selectively in defined tissues, for example, the tetracycline antibiotics in bone (see Antibiotics,tetracyclines). 

Species Tested. In addition to the variation in susceptibiUty to chemically induced toxicity among members within a given population, there may be marked differences between species with respect to the relative potency of a given material to produce toxic injury. These species differences may reflect variations in physiological and biochemical systems, differences in distribution and metaboHsm, and differences in uptake and excretory capacity. 

The realization of sensitive bioanalytical methods for measuring dmg and metaboUte concentrations in plasma and other biological fluids (see Automatic INSTRUMENTATION BlosENSORs) and the development of biocompatible polymers that can be tailor made with a wide range of predictable physical properties (see Prosthetic and biomedical devices) have revolutionized the development of pharmaceuticals (qv). Such bioanalytical techniques permit the characterization of pharmacokinetics, ie, the fate of a dmg in the plasma and body as a function of time. The pharmacokinetics of a dmg encompass absorption from the physiological site, distribution to the various compartments of the body, metaboHsm (if any), and excretion from the body (ADME). Clearance is the rate of removal of a dmg from the body and is the sum of all rates of clearance including metaboHsm, elimination, and excretion. 

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. 

Physiologically based toxicokinetic models are nowadays used increasingly for toxicological risk assessment. These models are based on human physiology, and thus take into consideration the actual toxicokinetic processes more accurately than the one- or two-compartment models. In these models, all of the relevant information regarding absorption, distribution, biotransformarion, and elimination of a compound is utilized. The principles of physiologically based pharmaco/ toxicokinetic models are depicted in Fig. 5.41a and h. The... 

Fig. 54 Fields of application and frequency distribution of biological-physiological detection methods.

Degree of polymerization distribution of a plant fructan (inulin) at increasing physiological age of the source remarkable performance of S-200 in the low dp range degree of polymerization distribution obtained from bad (P-6) and good (S-200 / P-6) resolution of high dp components... 

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