Metabolism and elimination

Pentobarbital is biotransformed by oxidation of the penultimate carbon of the methyl butyl side-chain to produce a mixture of alcohols, and by iV -hydroxylation. The alcoholic metabolites of pentobarbital are pharmacologically inactive. Approximately 86% of a radioactive dose is excreted in the urine in 6 days, about 1% as unchanged drug and up to 73% as the L- and D-diastereoisomers of 3 -hydroxypentobarbital in a 5.4 1 ratio, and up to 15% as JV-hydroxypentobarbital.9 None of these metabolites is eliminated as a conjugate. 

Amobarbital is extensively metabolized to polar metabolites in a process that is saturable and best described by zero-order kinetics at therapeutic doses.10 Two major metabolites are produced by hydroxylation and /V -glycosylation. 3 -Hydroxyamobarbital possesses pharmacological activity. Approximately 92% of a single dose is excreted in the urine with 5% excreted in the feces over a 6-day period. Approximately 2% is excreted unchanged in the urine, 30 to 40% is excreted as free 3 -hydroxyamobarbital, 29% as /V-glycosylamobarbital, and 5% as the minor metabolite, 3 -car-boxyamobarbital. 

Hardman, J.G. and Limbird, L.E., Eds., Goodman Gilman s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, 1996. 

MacDonald, R.L. and Barker, J.L., Anticonvulsant and anesthetic barbiturates different postsynaptic action in cultured mammalian neurons, Neurology, 29, 432-4-11, 1979. 

Dittert, L.W., Griffen, W.O., Jr., and Doluisio, J.T., Pharmacokinetics of pentobarbital after intravenous and oral administration, J. Pharm. Biopharm., 1, 5-16, 1973. 

In view of the fact that we have evolved in a manner in which we obtain our energy primarily by way of the gastrointestinal (GI) system, this route also became the most likely portal for the inadvertent introduction of toxic substances. Therefore, as a survival necessity, the body had to evolve a strategy for the early interception and processing of potentially lethal xenobiotic substances. Anatomically, this is accomplished by the hepatic-portal venous system, which delivers substrates absorbed from the gut directly to a succession of chemical-transforming enzyme systems located in the liver. 

The chemical modification of xenobiotics in the body is called biotransformation, metabolism, or metabolic clearance. Enzymes involved in metabolism are either membrane bound (e.g., endoplasmic reticulum and mitochondria) or freely soluble within the cytosol. Because these metabolic enzymes are not particularly substrate specific, they can metabolize compounds with fairly diverse chemical structures, including some endogenous compounds such as steroids, bile acids, and heme (endobiotics). 

In general, all biotransformation reactions can be assigned to one of two major categories called phase I and phase II reactions (Table 3.1). Phase I reactions are 

Interspecies and interindividual variability in drug metabolism is influenced by both genetic and environmental factors. The basal rate of drug metabolism in a particular individual is determined primarily by genetic constitution, but also varies with age, gender, and environmental factors such as diet, disease states, and concurrent use of other drugs. 

For most drugs, oxidative biotransformation is performed primarily by the mixed-function oxidase enzyme system, which is present predominantly in the smooth endoplasmic reticulum of the liver. This system comprises (1) the enzyme NADPH cytochrome P450 reductase (2) cytochrome P450, a family of heme-containing proteins that catalyze a variety of oxidative and reductive reactions and (3) a phospholipid bilayer that facilitates interaction between the two proteins. Important exceptions to this rule are ethyl alcohol and caffeine, which are oxidatively metabolized by enzymes primarily present in the soluble, cytosolic fraction of the liver. 

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Exposure to tetrachloroethylene as a result of vapor inhalation is foUowed by absorption into the bloodstream. It is partly excreted unchanged by the lungs (17,18). Approximately 20% of the absorbed material is subsequently metabolized and eliminated through the kidneys (27—29). MetaboHc breakdown occurs by oxidation to trichloroacetic acid and oxaHc acid. 

Little information on effects of DOSS on marine organisms are available [114-116]. A recently published paper deals with an intensive study of toxicity, bioaccumulation, metabolism, and elimination of DOSS in rainbow trout. The LCjq was determined to be 28 mg/L [116]. A very similar value was found for golden ide [117]. 

There are very limited data on the kinetics and metabolism of organotins in laboratory mammals. A widespread distribution of organotins throughout body tissues has been observed. Transplacental transfer seems to occur, whereas transfer across the blood-brain barrier is limited, since brain levels are usually low. The only compound for which data are available on metabolites is dibutyltin, which has butyl(3-hydroxybutyl)tin as its major metabolite. Limited information suggests quite rapid metabolism and elimination, with half-lives of several days. Much of an oral dose of dioctyltin was eliminated in the faeces, with the remainder in urine. 

To further investigate the role of the liver in brevetoxin metabolism, PbTx-3 was studied in the isolated perfused rat liver model (27, 28). Radiolabeled PbTx-3 was added to the reservoir of a recirculating system and allowed to mix thoroughly with the perfusate. Steady-state conditions were reached within 20 min. At steady-state, 55-65% of the delivered PbTx-3 was metabolized and/or extracted by the liver 26% remained in the effluent perfusate. Under a constant liver perfusion rate of 4 ml/min, the measured clearance rate was 0.11 ml/min/g liver. The calculated extraction ratio of 0.55 was in excellent agreement with the in vivo data. Radioactivity in the bile accounted for 7% of the total radiolabel perfused through the liver. PbTx-3 was metabolized and eliminated into bile as parent toxin plus four more-polar metabolites (Figure 3). Preliminary results of samples stained with 4-(p-nitrobenzyl)-pyridine (29) indicated the most polar metabolite was an epoxide. 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

During the past decade, numerous articles reviewing the effects of aging on pharmacokinetic processes (i.e., absorption, distribution, metabolism, and elimination) have been published [115 124h]. An outline of the observations made in these reports is supplied in Table 5. The absorption process is the only process that will be covered in depth in this chapter, as this is the process that can most easily be manipulated through formulation techniques. 

No mortality was found in any embryo exposed to the controls. On the contrary, all the embryos exposed to the non-diluted samples of penta-, octa-, and deca-BDE commercial mixtures were dead after 24 h (Fig. 10). When the untreated PBDEs samples were diluted at 50%, a gradient of toxicity was observed penta > octa > deca. After dilution at 5%, no embryos exposed to untreated samples were dead. In agreement with our results, it has been demonstrated that the toxicity of deca-BDE is commonly lower than for octa- and penta-BDE commercial products exposures with mammalian models [64]. The different toxicity found in mammalian models and also in zebrafish should be related to the higher accumulation of lower brominated congeners in the body, because of their greater partitioning and retention in lipid-rich tissues and lower rates of metabolism and elimination in relation to deca-BDE. 

Penicillamine Adsorption, Distribution, Metabolism, and Elimination Profile... 

Al-Attar, H.J. and C.O. Knowles. 1982. Diazinon uptake, metabolism, and elimination by nematodes. Arch. Environ. Contam. Toxicol. 11 669-673. 

Oral treatment of sheep and cattle (Bos spp.) with diflubenzuron is followed by absorption of the compound through the gastrointestinal tract, metabolism, and elimination of residues through the urine, feces, and, to a very limited extent, milk. Intact diflubenzuron is eliminated in the feces of orally dosed cattle and sheep (Ivie 1978). Major metabolites of diflubenzuron excreted by cattle and sheep result from hydroxylation on the difluorobenzoyl and chlorophenyl rings, and by cleavage between the carbonyl and amide groups to produce metabolites that are excreted free or as conjugates (Ivie 1978). Cattle dosed repeatedly with diflubenzuron had detectable residues only in liver... 

These in vivo and in vitro human metabolism studies indicate that pyrethroids undergo rapid metabolism and elimination as observed in rats, and qualitative metabolic profiles (e.g., kinds of metabolites) of pyrethroids are assumed to be almost the same between humans and rats, suggesting that a large database of animal metabolism of pyrethroids could provide useful information for the evaluation of behavior of pyrethroids in humans. Nowadays, human pesticide dosing studies for regulatory propose are severely restricted in the US, and thus detailed comparison of in vitro metabolism (e.g., metabolic rate constants of pathways on a step-by-step basis) using human and animal tissues could be an appropriate method to confirm the similarity or differences in metabolism between humans and animals. 

Toxicokinetic—The study of the absorption, distribution, metabolism, and elimination of toxic compounds in the living organism. 

The main disadvantage in using poly(acrylamide) systems is that they are not biodegradable and the monomers are toxic. Extensive purification is also required to remove the organic solvents, anionic surfactants, and residual monomers. Edman et al. [74] produced biodegradable poly(acryldextran) particles by incorporating dextran into the poly(acrylamide) chain. These particulate systems were metabolized and eliminated faster, both in vivo and in vitro, than poly(acrylamide) particles. 

The primary target for cyanide toxicity is the central nervous system following both acute and chronic exposure. Exposure to high doses of cyanide can rapidly lead to death (see Section 2.2). Cyanide is not stored in the organism and one available study indicates that >50% of the received dose can be eliminated within 24 hours (Okoh 1983). However, because of the rapid toxic action of cyanide, development of methods that would enhance metabolism and elimination of cyanide is warranted. 

Mehendale HM. 1977a. Chemical reactivity-absorption, retention, metabolism, and elimination of hexachlorocyclopentadiene. Environ Health Perspect 21 275-278. 

Pristine CNTs are hydrophobic and cause a lack of solubility in biological aqueous fluids such as blood. The poor solubility of CNTs in blood stream poses a major challenge to in vivo studies making behavior of CNTs difficult to predict and control (Kam et al., 2005 Zheng et al., 2003a, b). Therefore, modification of CNT surface to introduce hydrophilic, functional groups has been utilized in pharmaceutical applications (Lacerda et al., 2006). However, insufficient in vivo evaluation of both pristine and surface-modified CNTs has been performed to answer essential questions on CNT toxicology. Additional in vivo studies also required to devise the best method of administration, means of uptake, metabolism, and elimination of CNTs. The in vivo studies on CNTs performed to date are presented in Table 12.2. 

Along with metabolism and elimination determining extent to which PCBs are accumulated by fish, their lipid content is also important. Female fathead minnows accumulated about twice as much Aroclor 1248 and 1260 from water as males and this was due to greater lipid in females (20). 

The development of combinatorial chemistry and high throughput screening programmes has stimulated efforts to find experimental and computational models to estimate and predict drug absorption, distribution, metabolism and elimination based on drug physicochemical properties. 

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