Protein binding, tissue uptake

Plasma Vitamin B12 Binding Proteins and Tissue Uptake... 

The extent and degree of interactions between chiral macromolecules of the body and stereoisomers is a source of observable differences in isomeric drug distribution. Stereoselectivity in drug distribution may occur when tissue or protein binding or uptake is associated with structurally specific receptor, protein, or enzyme binding. Since only unbound or free drug is susceptible to elimination and distribution to receptors and other tissues and fluids, differences in the protein and tissue binding of stereoisomers are reflected in their overall pharmacokinetic profiles. 

Mechanism of Action Afibricacid derivative that inhibits lipolysis of fat in adipose tissue decreases liver uptake of free fatty acids and reduces hepatic triglyceride production. Inhibits synthesis of VLDL carrier apolipoprotein B. Therapeutic Effect Lowers serum cholesterol and triglycerides (decreases VLDL, LDL increases HDL). Pharmacokinetics Well absorbed from the GI tract. Protein binding 99%. Metabolized in liver. Primarily excreted in urine. Not removed by hemodialysis. Half-life 1.5 hr. 

Pfiarmacokineticsx Readily absorbed from the GI tract (high-fat meals delay absorption). Protein binding 85%. Widely distributed. Crosses the blood-brain barrier. Extensive intracellular tissue uptake. Metabolized in the liver to active metabolite. Excreted in urine eliminated in feces. Unknown if removed by hemodialysis. Half-life 16-69 hr. 

Active tissue uptake and binding to intra- and extravascular proteins, however, can substantially increase the volume of distribution of peptide and protein drugs, as for example observed with atrial natriuretic peptide (ANP) [56]. 

In intestinal mucosal cells, all vitamers of vitamin E cue incorporated into chylomicrons, and tissues take up some vitamin E from chylomicrons. Most, however, goes to the liver in chylomicron remnants, a -Tocopherol, which binds to the liver a-tocopherol transfer protein, is then exported in very low-density lipoprotein (VLDL) and is available for tissue uptake (Traber and Aral, 1999 Stocker and Azzi, 2000). Later, it appears in low-density Upoprotein (LDL) and high-density lipoprotein, as a result of metabolism of VLDL in the circulation. The other vitamers, which do not bind well to the a-tocopherol transfer protein, are not incorporated into VLDL, but are metabolized in the Uver and excreted. This explains thelower biological potency of the othervitcimers,despitesimilar, or higher, in vitro antioxidant activity. 

The divalent cation exists in both a nondiffusible form (tissues) and a diffusible form (blood) (Halbach and Clarkson 1978 Magos 1967) (see Section 2.3.2). The mechanism for the distribution of mercury and its compounds probably depends on the extent of uptake of the diffusible forms into different tissues or on the mercury-binding to protein-binding sites (sulfhydryl groups) in red cells and plasma proteins (Clarkson 1972b). 

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