SUBJECTS tissue distribution

There is limited information available regarding the distribution of methyl parathion after dermal exposure in humans. Two subjects, dermally exposed to methyl parathion, had 2.74 and 1.23 mg on their hands. Twenty-four hours after exposure, the serum levels were 0.027 and 0.032 mg/L, respectively (Ware et al. 1973). Twelve hours after cotton fields were sprayed, five men entered the treated fields for 5 hours. An average of 1.7 mg methyl parathion was detected on their hands. Serum concentrations averaged 0.156 mg/L in these subjects after 3 hours of exposure. Levels decreased to 0.1 and 0.002 mg/L at 2 and 24 hours postexposure, respectively (Ware et al. 1975). Although 0.5 mg methyl parathion was detected on the hands of four subjects, none was found in the serum (Ware et al. 1974). No information on the tissue distribution of methyl parathion in humans was found. 

The plasma levels of triprolidine hydrochloride were determined in 16 normal male subjects.12 When administered orally at a concentration of 3.75 mg triprolidine hydrochloride in 15 ml of syrup, peak plasma levels of 8.2 ng/ml were achieved in 2 hours with a drug half-life of 5 hours. The low plasma levels found indicate a large volume of tissue distribution which was consistent with data obtained from rat studies. 

In one subject who ingested an unknown amount, the serum concentration at 48 hours was 6.8 mmol/litre death occurred after 21 days and the following postmortem tissue distribution was reported serum 0.4 mmol/ litre, brain 0.35 to 0.85 mmol/kg, kidney 0.60 mmol/kg, liver 0.22 mmol/ kg, lung 0.51 mmol/kg (A. Amidsen et al., Acta psychiat. scand., 1974, 255, Suppl. 4, 25-33). 

The following postmortem tissue distribution was reported in a female subject who had been receiving 300 mg of zimeldine daily and had been found drowned blood, zimeldine 0.3 pg/ml, norzimeldine 0.9 pg/ml bile, zimeldine 5.0pg/ml, norzimeldine 15pg/ml liver, zimeldine 4.0pg/g, norzimeldine 16pg/g (R. Geyer, Bull. int. Ass. forens. Toxicol., 1981, 76(2), 30-31). 

Determination of exposure and toxic effects of chemicals also requires knowledge of toxicokinetics. Toxicokinetics is the study of changes in the levels of toxic chemicals and their metabolites over time in various fluids, tissues, and excreta of the body, and determines mathematical relationships to explain these processes. These processes depend upon uptake rates and doses, metabolism, excretion, internal transport, and tissue distribution. Methods for determining these processes include studies with laboratory animals, volunteer human subjects, persons accidentally exposed to high doses of chemicals, and experiments with tissue or organs cultured in the laboratory. Computer simulations of such processes are often formulated using complex mathematical equations. 

Tissue Disposition and Pharmacological Effects of Liposomes In Vivo -Since the initial publication of studies involving injection of liposome-entrapped substances In vivo,H 71.72 there has been an increasing number of studies on both the altered tissue distribution and also on the increased pharmacological efficacy of encapsulated agents. The subject has been reviewed recently.13 15,20, The most important points for future consideration include the permeability properties of liposomes in a physiological environment, their interaction with plasma components, the role of liposome size and chemistry in determining the rate of removal from the circulation and their tissue localization at the cellular level. 

The challenge in the analysis of quantic (one sample/subject) data is further complicated when tissue sampling (e.g., in tissue distribution studies) is involved, and the ratio of tissue to plasma concentrations is the object of the investigation. Equally, only one tissue sample/subject is obtained in such studies because the animal is usually killed. 

The majority of the 14C-human ADME studies are conducted with a small number of healthy adult subjects (often between 6-8) and if bile collection is needed, a small group of additional subjects are included [228], Traditionally, due to ethical reasons, male subjects are selected for the 14C-ADME studies. Before the start of the 14C-ADME studies, study sponsors have the responsibility to determine stability of the radiolabel, purity of the radiolabel (distinguishing degradants from metabolites is very important), and conduct tissue distribution studies in nonclinical species preferably using quantitative whole-body autoradiography (QWBA) to detect radioactivity in tissues, organs, and excreta to determine the safe radioactivity dose. Nonclinical tissue distribution study data are extrapolated and used to show that radioactivity exposure of a specific tissue/organ will be well below the allowable limits to humans [229,230], Most of the 14C-human ADME studies consider a total radioactivity dose of 100[tCi or less to be safe [231],... 

Modifications in the base, sugar, and phosphate moieties of oligonucleotides and oligonucleotide conjugates have been reported. The subjects of medicinal chemical programs include approaches to create enhanced affinity and more selective affinity for RNA or duplex structures the ability to cleave nucleic acid targets enhanced nuclease stability cellular uptake and distribution and in vivo tissue distribution, metabolism, and clearance. 

Radioactivity profiling in plasma, urine, bile, and feces of appropriate animals and human subjects from mass balance studies enable a quantitative evaluation of the absorption, tissue distribution, and excretion of a drug candidate. The data can be supplemented with tissue distribution information from whole-body analysis and the further defining the sites of absorption and excretion in surgically prepared animals. 

The only data that have been provided on Gd levels in plasma and urine of healthy subjects were those of Allain et al. [16] reporting normal concentrations of the element in these biological fluids to be <0.3 p.g/liter. Data on the tissue distribution of Gd are scarce. As for some other medium lanthanides, i.e., the subgroup of lanthanides that comprises the elements from europium (Eu) to holmium (Ho), the element is supposed to be equally deposited in the liver and the skeleton [2]. Administration of Gd-DOTA and Gd-DTPA contrast agents in rats resulted in a 0. l-1.0% retention in liver and spleen [17]. 

Clinical studies investigated the antioxidative effects of antioxidant supplementation of humans on ex vivo LDL oxidation [48-52], We have shown that dietary supplementation of p-carotene of healthy subjects resulted in a moderate inhibitory effect on the susceptibility of LDL to oxidative modification [53-55] in some, but not in all studied subjects. The combination of carotenoids with vitamin E, in contrast, demonstrated a synergistic inhibitory effect on LDL oxidation in all studied cases [56], We showed that supplementation of vitamin E of atherosclerotic apolipoprotein E-deficient mice (25 pg/mouse/day for 3 months) inhibited LDL oxidation by 40% and the atherosclerotic lesion area by 35% [57], In humans, unlike in animal models, both vitamin E and carotenoids did not significantly reduce atherosclerosis in primary prevention trials [58], This result may be related to insufficient absorption, insufficient potency, and inappropriate tissue distribution,... 

JC LinneU, AV Hoffbrand, HA-A Hussein, U Wise, DM Matthews. Tissue distribution of coenzyme and other forms of vitamin B,2 in control subjects and patients with pernicious anemia. Chn Sci Mol Med 46 163-172, 1974. 

The levels of veterinary drug residues are subject to pharmacokinetic parameters absorption, tissue distribution, metabolism and excretion. The degree of absorption depends on the physico-chemical properties of the compounds and the method of administration, which may, for example, be ... 

There is a decrease in the plasma concentration of vitamin Bg with increasing age, and some studies have shown a high prevalence of abnormal transaminase activation coefficient in elderly subjects, suggesting that the elderly may be at risk of vitamin Bg deficiency. It is not known whether this reflects an inadequate intake, a greater requirement, or changes in the tissue distribution and metabolism of the vitamin with increasing age. 

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