Distribution to tissues

Glycerol may be picked up by liver and converted to dihydroxyacetone phosphate (DHAP) for gluconeogenesis, and the fetty adds are distributed to tissues that can use them. Free fatty acids are transported through the blood in association with serum albumin. 

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. 

The anthracyclines, apart from valrubicin, are administered intravenously. Doxorubicin is rapidly distributed to tissues and slowly eliminated in faeces and urine with an elimination half-life of several days. Daunorubicin undergoes extensive metabolism in the liver, among others to the active daunorubi-cinol, and is eliminated as inactive products with an elimination half-live of approximately 30 hours. Epimbicin and idambicin have similar kinetic profiles as daunombicin with respectively epirubici-nol and idarubicinol as their major metabolic products. The kinetic behavior of mitoxantrone resembles more that of doxorubicin with a very slow elimination from the body mainly as parent compound or as inactive metabolites. The anthracyclines do not cross the blood-brain barrier. 

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). 

Pharmacokinetics Metabolized to thiamine pyrophosphate (active) in the liver. At dietary levels thiamine is completely distributed to tissues. At pharmacologic doses, excess thiamine is excreted in urine. 

Mechanism of Action Avirustatic antiviral that is converted to acyclovir triphosphate, becoming part of the viral DNA chain. Therapeutic Effect Interferes with DNA synthesis and replication of herpes simplex virus and varicella-zoster virus. Pharmacokinetics Rapidly absorbed after PO administration. Protein binding 13%-18%. Rapidly converted by hydrolysis to the active compound acyclovir. Widely distributed to tissues and body fluids (including cerebrospinal fluid CSF ). Primarily eliminated in urine. Removed by hemodialysis. Half-life 2.5-3.3 hr (increased in impaired renal function). 

Some drugs such as digoxin and lithium take several hours to distribute to tissues. Digoxin samples should be taken at least 6 hours after the last dose and lithium just before the next dose (usually 24 hours after the last dose). Aminoglycosides distribute quite rapidly, but it is still prudent to wait 1 hour after giving the dose before taking a sample. 

Digoxin, the only cardiac glycoside used in the USA, is 65-80% absorbed after oral administration. Absorption of other glycosides varies from zero to nearly 100%. Once present in the blood, all cardiac glycosides are widely distributed to tissues, including the central nervous system. 

Shetty B, Kosa M, Khalil DA, Webber S. Preclinical Pharmacokinetics and Distribution to Tissue of AG1343, an inhibitor of human deficiency virus type 1 protease. Antimicr. Ag. and Chemoth. 1996 40 110-114. 

Barbiturates such as phenobarbital are weak acids. The toxicity of the barbiturate is mainly the result of the effects on the central nervous system. Only the nonionized form of the drug will distribute into the central nervous system. The proportion ionized will depend on the pKa and the pH of the blood. By increasing the pH of the blood using sodium bicarbonate administration to the poisoned patient, ionization of the barbiturate will be increased and distribution to tissues such as the brain will be decreased. Urinary excretion of the barbiturate will also be increased because the urinary pH will be increased. 

Chlorodifluoromethane is very rapidly cleared from the blood of rats and rabbits exposed by inhalation. Little distribution to tissues or metabolism occurs in rats, with recoveries from expired air as CO2 in 15-24 h and in the urine, being about 0.1% and 0.02% of the dose, respectively (lARC, 1986). 

Fentanyl is highly lipophilic. It is rapidly distributed to tissues such as the brain, heart, kidneys, and lungs, followed by slower movement into muscle and fat. 

Absorption into the bloodstream is the first step for drugs to reach their targets followed by distribution to tissues. The drugs are then metabolized into more readily excreted forms. All of these aspects are significantly mediated or... 

Flavonoids can bind to plasma albumin,41 possibly decreasing their diffusion into cells.42 A 10% reduction of plasma albumin in older individuals43 44 could impact flavonoid distribution to tissues however, in fact, age-related decreases of albumin binding appear to have a minimal impact on the Vd of drugs 45... 

The initial rapid distribution to tissues dominates plasma clearance (>90%), which is characterized by a near-complete distribution with a several-fold log decline of plasma ISIS 104838 concentrations over a 24-h period. The rapid and complete distribution phase is similar to that of the first-generation PS oligodeox-ynucleotides. However, plasma concentrations of 2 -MOE partially modified ASOs... 

While distribution to tissues relies on the mechanism of plasma clearance, whole-body clearance is the result of metabolism and the excretion of low molecular-weight oligonucleotides. Ubiquitous nucleases are known to metabolize oligonu-... 

In hepatocytes, vitamin E can take two routes. A fraction of it is packaged as VLDL and reenters the circulation, while excess is excreted in the bile. Plasma lipolysis of the VLDL particle again results in release not only of lipids, but also of vitamin E, with the remainder left with the LDL particles. This fraction can be further distributed to tissues via LDL receptor-mediated endocytosis or transferred between lipoproteins, mainly to HDL, by plasma lipid transfer proteins. Thus, mobilization of vitamin E from intestinal and liver... 

Hepatic Effects. DNOC is a yellow compound that stains human (Hunter 1950) and animal (Ambrose 1942) skin on contact. Absorption of DNOC by any route and subsequent distribution to tissues results in a characteristic yellow staining of visceral organs and tissues including the conjunctiva and sclera of the eye (Ibrahim et al. 1934 Pollard and Filbee 1951), blood serum, skeletal tissue, and urine (Ambrose 1942). The yellow staining of the skin and sclera of patients exposed to DNOC prompted physicians to test for liver effects. Results for the index index and the Van den Bergh tests have been consistently negative (Dodds and Robertson 1933 Gordon and Wallfield 1935 Plotz 1936). 

The alkanes, cycloalkanes, and aromatic compounds present in diesel are lipophilic and tend to distribute to tissues with higher adipose tissue content. The reversibility and short-term nature of many effects observed during acute exposure indicate that retention of the principal diesel fuel components in body tissues is limited. 

Toluene is readily absorbed from the lung and gastrointestinal tract, although studies in animals suggest absorption occurs more slowly in the gastrointestinal tract. Slow absorption also occurs through skin. Studies of humans and animals indicate that inhaled toluene distributes to tissues that are high in fat content (e.g., body fat, bone marrow, and brain) or well supplied with blood (e.g., liver). It seems reasonable to assume that similar distribution would occur for other routes of exposure. 

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