Brain inhalant distribution

Compound MEUOES (mgm- ) Vapor pressure (2a C, mmHg) Inhaled dose Proportion absorbed dose absorbed (%) (%) Eliminated Metabolized unchanged Half-life (h) Brain-blood distribution ratio (deaths) Partition coefficient (blood-gas) (37-C)... 

Hydrogen sulfide is widely distributed in the body. Sulfides have been found in the liver, blood, brain, lungs, spleen, and kidneys of humans who died after accidental inhalation exposure. 

The distribution of anesthetic throughout the entire body may be viewed as an equilibration process (Fig. 7.1.13), with tissues characterized by high blood flows reaching equilibration faster than muscle and fatJ4 Nevertheless, an anesthetic that is excessively soluble in blood will not partition substantially into brain and other tissues. The anesthetic properties of nitrous oxide and diethyl ether have been known since the 1840s. Zeneca Pharmaceuticals introduced the first modem inhalation anesthetic fluothane in 1957. Methoxyfluorane followed in 1960, enflurane 1973, isoflurane 1981, desflurane by Anaquest (Liberty Comer, NJ) in 1992, and sevoflurane by Abbott Laboratories in 1995J6 ... 

Acrylonitrile is rapidly distributed throughout the body after inhalation exposure. Measurable amounts of acrylonitrile derived radiolabel were present in the brain, stomach, liver, kidney, lung and blood within 1 hour of initiation of exposure (Pilon et al. 1988b). 

Brain, J.D., Knudson, D.E., Sorokin, S.P. and Davis, M.A. (1976). Pulmonary distribution of particles given by intratracheal instillation or be aerosol inhalation. Environ. Res. 11 13-33. 

The toxicokinetics of disulfoton in humans and animals depends on its physicochemical characteristics and its metabolism. The lipophilicity of disulfoton indicates that the insecticide should be easily absorbed by oral, inhalation, and dermal routes. No bioavailability data were located for inhalation and dermal exposure. However, disulfoton is almost completely absorbed from the gastrointestinal tract within 2 days after oral exposure. Animal studies suggest that disulfoton is widely distributed primarily to the liver and in smaller quantities to the kidney, fat, skin, muscle, brain, and other organs. Disulfoton and/or its metabolites are excreted mainly in the urine of humans and animals, with minor amounts excreted in the feces and expired air. 

Absorption, Distribution, Metabolism, and Excretion. No studies were located regarding the absorption, distribution, metabolism, and excretion of disulfoton by humans or animals after inhalation or dermal exposure. Limited data exist regarding the absorption, distribution, and excretion after oral exposure to disulfoton. Data on levels of disulfoton and metabolites excreted in urine and expired air suggest that some almost complete absorption of an administered dose of disulfoton over 3-10 days (Lee et al. 1985 Puhl and Fredrickson 1975). The data are limited regarding the relative rate and extent of absorption. Animal data suggest that disulfoton and/or its metabolites are rapidly distributed to the liver, kidney, fat, skin, muscle, and brain, with peak levels occurring within 6 hours (Puhl and Fredrickson 1975). Elimination of disulfoton and metabolites occurs primarily in the urine, with >90% excreted in the urine in 3-10 days (Lee et al. 1985 Puhl and Fredrickson 1975). 

After whole-body autoradiography to study the distribution of " C-labeled chloroform in mice, most of the radioactivity was found in fat immediately after exposure, while the concentration of radioactivity in the liver increased during the postanesthetic period, most likely due to covalent binding to lipid and protein in the liver (Cohen and Hood 1969). Partition coefilcients (tissue/air) for mice and rats were 21.3 and 20.8 for blood 19.1 and 21.1 for liver 11 and 11 for kidney and 242 and 203 for fat, respectively (Corley et al. 1990). Arterial levels of chloroform in mongrel dogs reached 0.35-0.40 mg/mL by the time animals were in deep anesthesia (Chenoweth et al. 1962). Chloroform concentrations in the inhaled stream were not measured, however. After 2.5 hours of deep anesthesia, there were 392 mg/kg chloroform in brain tissue, 1,305 mg/kg in adrenals, 2,820 mg/kg in omental fat, and 290 mg/kg in the liver. 

Inhaled nicotine is efficiently delivered to the brain (see chapter by Benowitz, this volume) where it selectively interacts with its central targets, the neuronal nicotinic acetylcholine receptors (nAChRs). The multiple subtypes of uAChR (see chapter by Collins et al, this volume) all bind nicotine but with different affinities, depending on the subunit composition of the uAChR. Binding may result in activation or desensitisation of uAChRs, reflecting the temporal characteristics of nicotine dehvery and local concentration of nicotine. Another level of complexity of the actions of nicotine reflects the widespread and non-uniform distribution of uAChR subtypes within the brain, such that nicotine can influence many centrally regulated functions in addition to the reward systems. In this chapter, we address the consequences of nicotine interactions with nAChRs at the molecular, cellular and anatomical levels. We critically evaluate experimental approaches, with respect to their relevance to human smoking, and contrast the acute and chronic effects of nicotine. 

Distribution, including accumulation of an absorbed substance, will be the same irrespective of the route of administration. However, distribution and accumulation at the site of apphcation (inhalation, oral, dermal) may depend on the route of administration. In such cases, local accumulation may occur and may be responsible for tissue damage. In these cases, systemic toxicokinetics of the substance may be of limited relevance for the risk assessment. It is generally not cmcial for risk assessment to determine the precise tissue distribution profile for a substance. In certain special cases, however, specific tissue distribution studies may assist or even be essential for the interpretation of available toxicological data. For example, it may be of interest to know whether the substance will cross the blood-brain barrier, the placenta barrier, or will accumulate in specific tissues. 

Nicotine is well absorbed from the mucous membranes in the oral cavity, gastrointestinal tract, and respiratory system. If tobacco smoke is held in the mouth for 2 seconds, 66 to 77% of the nicotine in the smoke will be absorbed across the oral mucosa. If tobacco smoke is inhaled, approximately 90 to 98% of the nicotine will be absorbed. Nicotine is distributed throughout the body, readily crossing the blood-brain and placental barriers. The liver, kidney, and lung metabolize approximately 80 to 90% of the alkaloid. The kidney rapidly eliminates nicotine and its metabolites. 

Ensuring an adequate depth of anesthesia depends on achieving a therapeutic concentration of the anesthetic in the CNS. The rate at which an effective brain concentration is achieved (ie, time to induction of general anesthesia) depends on multiple pharmacokinetic factors that influence the brain uptake and tissue distribution of the anesthetic agent. The pharmacokinetic properties of the intravenous anesthetics (Table 25-1) and the physicochemical properties of the inhaled agents (Table 25-2) directly influence the pharmacodynamic effects of these drugs. These factors also influence the rate of recovery when the administration of anesthetic is discontinued. 

Following inhalation exposure of rats to 406 ppm [2600 mg/m ] carbon tetrachloride for 4 h, the blood level was 10.5 mg/L, but dropped to 50% of this value in less than 30 min (Frantik Benes, 1984). Carbon tetrachloride, administered by inhalation to rats, mice or monkeys, is distributed to most tissues, including fat, liver, brain, bone marrow and kidney (McCollister et al., 1951 Bergman, 1984 Paustenbach et al., 1986). In mice exposed to [ CJcarbon tetrachloride, much of the radioactivity became non-volatile and a portion appeared to be non-extractable (Bergman, 1984). 

After absorption, methyl bromide or metabolites are rapidly distributed to many tissues including the lung, adrenal gland, kidney, liver, nasal turbinates, brain, testis and adipose tissue. In an inhalation study in rats, the methyl bromide concentrations in tissues reached a maximum after 1 h of exposure, but decreased rapidly. Methyl bromide is probably metabolized by glutathione conjugation, the fonned. S -mcthylglutathione being sequentially catabolized to. S -methyl-L-cystcinc and then to carbon dioxide. 

Trichloroethane inhaled by animals distributes primarily into fat, liver and, to a lesser extent, kidney and brain, and is rapidly cleared after cessation of exposure (Holmberg etal., 9Tl-, Savolainen etal., 911-, Schumann etal., 1982a Takahara, 1986). A linear relationship between exposure concentration and tissue concentration was found (Holmberg et al., 1977). 

No quantitative information on absorption, distribution, metabolism, and excretion of white phosphorus following inhalation, oral, dermal, and dermal bum exposure was located. Studies in which 32P-labeled white phosphorus was orally administered to animals demonstrated that the label was widely distributed throughout the body, with some of the highest concentrations in the liver, kidney, blood, spleen, and brain (Cameron and Patrick 1966 Lee etal. 1975). 

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