Distribution mechanisms pharmacokinetics

In the present compilation of the distribution and pharmacokinetic data of a dozen xenobiotics studied in the dogfish shark, this species yielded excellent data consistent with what we know from similar studies on terrestrial mammals. The data from the shark occasionaly provided information not available in other animals. Major transport parameters in this fish were shown to be similar to those found in mammals. This aquatic organism handles lipid-soluble pollutants by sequestering them in its fatty liver. Together with a previous summary (23) we have now studied about three dozen xenobiotics in this species. Because of its ease of handling, low cost, abundance, predictive value of transport mechanisms, and well-developed pharmacokinetics, the dogfish shark is an ideal fish species to use as a model to study aquatic pollutants. 

The concept behind the use of liposomes as carriers of drugs and macromolecules is related to an expected protection of the encapsulated molecules in the blood stream, an altered tissue distribution and pharmacokinetics, as well as an increased uptake into cells by mechanisms that are not normally available for these molecules. Some of these expectations have been verified through studies in various laboratories during the last few years. Such studies have shown that liposome encapsulation can alter drastically the pharmacokinetics and tissue disposition of the encapsulated substances, it can enhance their uptake into cells, and it can Increase their pharmacological efficacy. Several recent reviews have discussed these early results in considerable detail. 20... 

Poulin, P. Thiel, F.-P., Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution, J. Pharm. Sci. 91, 129-156 (2002). 

Nonetheless the approach can provide - both routinely and rapidly - large amounts of pharmacokinetic or other distribution information on several compounds without significantly increasing the burden on the animals, whilst also minimizing the number of animals used. It is common to include a compound of known pharmacokinetics that acts as a control in each of these studies. This can help in identifying when the co-administered compounds have changed the kinetics. However, such marker compounds will not necessarily highlight problems with compounds that are subject to different clearance mechanisms [35],... 

Repeat dose pharmacokinetic studies were undertaken in Sprague-Dawley rats and in monkeys. Biodistribution studies were carried out in both normal and knockout mice, with the majority of product distributed to the liver. No specific studies on product metabolism or excretion were undertaken, as the protein is almost certainly degraded via normal protein degradation mechanisms. 

Although there is no reason to suspect that the pharmacokinetics of 1,4-dichlorobenzene differs in children and adults, scant data are available to support or disprove this statement. Studies of absorption, distribution, metabolism, and excretion in children would aid in determining if children are at an increased risk, particularly if conducted in an area where a high-dose acute or low-dose chronic exposure to an environmental source were to occur. With regard to exposure during development, additional research on maternal and fetal/neonatal toxicokinetics, placental biotransformation, the mechanism of... 

Elizabetli, C.M., Della, P., Oscar Ploeger, B.A. and Voskuyl, R.A. (2007) Mechanism-based pharmacokinetic-pharmacodynamic modeling hiophase distribution, receptor theory, and dynamical systems analysis. Annual Review of Pharmacology and Toxicology, 47, 357-400. 

Mechanism of Action A benzimidazole carbamate anthelmintic that degrades parasite cytoplasmic microtubules, irreversibly blocks cholinesterase secretion, glucose uptake in helminth and larvae (depletes glycogen, decreases ATP production, depletes energy). Vermicidal. Therapeutic Effect Immobilizes and kills worms. Pharmacokinetics Poorly and variably absorbed from GI tract. Widely distributed, cyst fluid and including cerebrospinal fluid (CSF). Protein binding 70%. Extensively metabolized in liver. Primarily excreted in urine and bile. Not removed by hemodialysis. Half-life 8-12 hr. 

Mechanism of Action A direct thrombin inhibitor that reversibly binds to thrombin-active sites. Inhibits thrombin-catalyzed or thrombin-induced reactions, including fibrin formation, activation of coagulant factors V, VIII, and XIII also inhibits protein C formation, and platelet aggregation. Therapeutic Effect Produces anticoagulation. Pharmacokinetics Following IV administration, distributed primarily in extracellular fluid. Protein binding 54%. Metabolized in the liver. Primarily excreted in the feces, presumably through biliary secretion. Half-life 39-51 min. 

Mechanism of Action A second-generation cephalosporin that binds to bacterial cell membranes and inhibits cell wall synthesis. Therapeutic Effect Bactericidal. Pharmacokinetics Well absorbed from the GI tract. Protein binding 25%. Widely distributed. Primarily excreted unchanged in urine. Moderately removed by hemodialysis. Half-life 0.6-0.9 hr (increased in impaired renal function). 

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