Tissues, protein distribution

Rapidly and widely distributed to tissues. Protein binding 65%. Metabolized in the liver to active metabolite. Eliminated in urine and feces. Half-life 10-12hr(increased in the elderly). 

Propiopromazine has been used in all the domesticated animals. Although very limited information is available on the absorption, distribution, metabolism, and elimination of propiopromazine in animals, several studies (103) have reported the presence of propiopromazine in pig kidney collected from abattoirs, so that human exposure should therefore be presumed. Both pigs and horses are able to metabolize propiopromazine, at least in part. The drug binds extensively to tissue proteins, and also accumulates in fatty tissues. 

Albumin is the most abundant protein in human and other animal plasma. It is estimated that up to 40% of the total albumin in humans is in circulation transporting essential nutrients, especially those that are sparingly soluble in aqueous-based plasma. For example, the fatty acids, which are important fuel molecules for the peripheral tissue, are distributed by albumin. In addition, albumin is the plasma transport protein for other substances including bilirubin, thyroxine, and steroid hormones. Also, many drugs including aspirin, sulfanilamides, clofibrate, and digitalis bind to albumin and are most likely carried to their sites of action by the protein. 

Kuznicki J, Filipek A, Heimann P, Kaczmarek L, Kaminska B. 1989a. Tissue specific distribution of calcyclin-10.5 kDa Ca2+-binding protein. FEBS Lett 254(1-2) 141—144. 

It is possible to predict what happens to Vd when fu or fur changes as a result of physiological or disease processes in the body that change plasma and/or tissue protein concentrations. For example, Vd can increase with increased unbound toxicant in plasma or with a decrease in unbound toxicant tissue concentrations. The preceding equation explains why because of both plasma and tissue binding, some Vd values rarely correspond to a real volume such as plasma volume, extracellular space, or total body water. Finally interspecies differences in Vd values can be due to differences in body composition of body fat and protein, organ size, and blood flow as alluded to earlier in this section. The reader should also be aware that in addition to Vd, there are volumes of distribution that can be obtained from pharmacokinetic analysis of a given data set. These include the volume of distribution at steady state (Vd]SS), volume of the central compartment (Vc), and the volume of distribution that is operative over the elimination phase (Vd ea). The reader is advised to consult other relevant texts for a more detailed description of these parameters and when it is appropriate to use these parameters. 

Drugs that show extensive tissue binding are said to have an apparent volume of distribution many times the total body size. For example, digoxin (see Chapter 35), which binds to plasma protein to the extent of 23%, has an apparent volume of distribution of 8 1/kg. The volume of distribution of drugs that do not bind to plasma or tissue proteins varies between the extracellular fluid volume (16 liters) and the total body water (42 liters). Insulin, sodium, and iodine are confined to the extracellular water, whereas caffeine and ethanol are distributed in the total body water. 

Because lithium is not bound to any plasma or tissue proteins, it is widely distributed throughout the body. Lithium ions are eliminated mainly by the kidneys. There is a direct relationship between the amount of sodium chloride ingested and the fraction of filtered lithium resorbed, in that, the lower the sodium intake, the greater is the lithium retention. The contraindications are significant cardiovascular or renal diseases that would compromise its excretion. 

Once absorbed into the blood, all cardiac glycosides are widely distributed to tissues, including the central nervous system. Their volumes of distribution differ, however, depending on their tendency to bind to plasma proteins versus tissue proteins. 

The distribution of drugs is affected by the circulating plasma that transports them to sites of action, metabolism, and excretion. After absorption, most drugs are partially or almost totally bound to plasma and tissue proteins. The portion that is protein bound is pharmacologically inactive. It serves as a reservoir from which the usually much smaller unbound active fraction can be replenished as the free drug is metabolized and excreted (51). 

Rats and mice were intraperitoneally injected with 1.2 mg [ C]-1,1 -dichloroethane/kg and sacrificed 22 hours later. 1,1-Dichloroethane was covalently bound to proteins, RNA, and DNA of liver, kidney, lung, and stomach. The extent of binding was greatest in the tissue proteins and least in the DNA. Binding to rat and mouse DNA was greatest in the stomach and liver, respectively (Colacci et al. 1985). Although distribution of 1,1-dichloroethane very likely occurs to other tissues, the liver, kidney, lung, and stomach were the only tissues analyzed in this study. 

Drug distribution is affected by many factors/ including plasma or tissue protein binding/ body weight/ body composition/ and body fluid spaces (8). Of these/ total body weight/ muscle masS/ and fat composition are the major determinants of drug distribution/ and women may differ from men in both of these factors. 

Second, tissue protein binding of medication can affect drug disposition in the elderly patient. For example, amiodarone binds strongly to tissue proteins, which greatly increases its volume of distribution. In the elderly or chronically ill patient, tissue proteins may change or decline, which can also affect the serum levels of medications. 

The apparent volume of distribution at steady state (Tss) is influenced by plasma and tissue protein binding according to equation ... 

Volume of Distribution Volume of distribution is the space in which the drug appears to distribute. Volume of distribution is a complex relationship between water and lipid solubility, drug binding to plasma and tissue proteins, and active transport systems. 

Studies of the distribution of [3H]ginsenoside Rgl following intravenous injection have been performed in mice (80). Tissue radioactivity was greatest in the kidney, followed by the adrenal gland, liver, lungs, spleen, pancreas, heart, testes, and brain. Plasma protein binding was 24%, and tissue protein binding was 48% in the liver, 22% in testes, and 8% in the brain. 

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