Distribution and elimination

Whereas much is known of the absorption and metabolism of isothiocyanates, virtually nothing is known of the absorption and metabolism of the other products arising from the breakdown of glucosinolates (e.g. nitriles, thiocyanates). This is probably because of two main reasons first, the majority of research has focused on isothiocyanates due to their potent anti-cancer activities, and second, there is a lack of methods for measuring other breakdown products. In particular, the dithiol condensation reaction is the most reported approach but is specific for isothiocyanates. 

The urinary yield of isothiocyanates depends on the form in which the dose is given. The urinary yield of total isothiocyanates (determined using the dithiol cyclo condensation method) from an oral dose of sulphoraphane was 80% but for the parent glucosinolate 

Humans do not have the ability to synthesize retinol (vitamin A) and have thus evolved to derive this compound from the diet, either directly as preformed retinol from foods of animal origin or from the metabohsm of carotenoids primarily derived from plant tissues. Several hundred carotenoids have been isolated, named and their structures elucidated, but only a few have a known biochemical role in human metabolism or are present in the diet in sufficient quantities to be detected in plasma (Khachik et al. 1992). The chemical 

Structure of carotenoids means that they range in colour from pale yellow to intense red-orange and are most abundant in green photosynthetic plant tissues where their natural colour is masked by chlorophyll or in fruits, roots, flowers, seeds, leaves, etc where the colour provides visual cues as to ripeness, suitability as food, guidance for pollinating insects, photoprotectants and indicators of senescence. Because of the natural occurrence of carotenoids some are also permitted food colourants and maybe added to foods either as the isolated compound, ester or as stabilized dispersible formulations. The amounts added are usually small because some of the carotenoids are very intensely coloured. 

The main dietary carotenoids are lycopene (linear, no substitutions), fl-carotene and a-carotene (ring closure at both ends, no substitutions), P-cryptoxanthin (ring closure at both ends, substitution in the 3 position), lutein (ring closure at both ends, substitutions in the 3 and 3 positions) and canthaxanthin (ring closure at both ends, [O] substitutions in the 4 and 4 positions). In some tissues, particularly flower petals, the hydroxylated carotenoids may also be present as mono- or di-acyl esters, most commonly with C16 fatty acids. Further oxidation of the terminal ring may occur to produce the mono- and di-epoxides. For an exhaustive list of carotenoids, the Key to Carotenoids (Straub 1987) is a recommended reference source. 

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In cases of all but intravenous adininistration, dosage forms must make the active moiety available for absorption, ie, for dmg release. This influences the bioavailabiUty and the dmg s pharmacokinetic profile. Ideally the dmg is made available to the blood for distribution and elimination at a rate equal to those processes. Through technological developments dmg product design can achieve release, absorption, and elimination rates resulting in durations of activity of 8—12 hours, ie, prolonged action/controlled release dmg products (21,22). Such products improve the compliance rate of dmg usage by patients. 

It is important to appreciate that the magnitude of the absorbed dose, the relative amounts of bio transformation product, and the distribution and elimination of metaboUtes and parent compound seen with a single exposure, may be modified by repeated exposures. For example, repeated exposure may enhance mechanisms responsible for biotransformation of the absorbed material, and thus modify the relative proportions of the metaboUtes and parent molecule, and thus the retention pattern of these materials. Clearly, this could influence the likelihood for target organ toxicity. Additionally, and particularly when there is a slow excretion rate, repeated exposures may increase the possibiUty for progressive loading of tissues and body fluids, and hence the potential for cumulative toxicity. 

Kinetic studies Rats/rniee One day to weeks Absorption, distribution, and elimination... 

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

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

FIG. 2 Mechanisms of drug transfer in the cellular layers that line different compartments in the body. These mechanisms regulate drug absorption, distribution, and elimination. The figure illustrates these mechanisms in the intestinal wall. (1) Passive transcellular diffusion across the lipid bilayers, (2) paracellular passive diffusion, (3) efflux by P-glycoprotein, (4) metabolism during drug absorption, (5) active transport, and (6) transcytosis [251]. 

Smith, T.W. Lloyd, B.L. Spicer, N. and Haber, E. Immuno-genicity and kinetics of distribution and elimination of sheep digoxin-specific IgG and Fab fragments in the rabbit and baboon. Clin Exp Immunol 36 384-396, 1979. 

Abou-Donia MB, Suwita E, Nomeir AA. 1990a. Absorption, distribution, and elimination of a single oral dose of [14C]tri-orf/ o-cresyl phosphate in hens. Toxicology 61 13-25. 

Kusuhara, H. and Y. Sugiyama. Role of transporters in the tissue-selective distribution and elimination of drugs transporters in the liver, small intestine, brain and kidney. J. Control. Release 2002, 78, 43-54. 

Thus, %F is defined as the area under the curve normalized for administered dose. Blood drug concentration is affected by the dynamics of dissolution, solubility, absorption, metabolism, distribution, and elimination. In addition to %F, other pharmacokinetic parameters are derived from the drug concentration versus time plots. These include the terms to describe the compound s absorption, distribution, metabolism and excretion, but they are dependent to some degree on the route of administration of the drug. For instance, if the drug is administered by the intravenous route it will undergo rapid distribution into the tissues, including those tissues that are responsible for its elimination. 

There is evidence for the presence of other human OATPs including OATP-D [30], OATP-F (NM 017435] [39] and OATPRP4 (NM 030958). Further studies are required to determine the impact of these transporters on the drug distribution and elimination. 

Melancon, M.J. Jr., Lech, J.J. (1978) Distribution and elimination of naphthalene and 2-methylnaphthalene in rainbow trout during short and long-term exposures. Arch. Environ, Contam. Toxicol. 7, 207. 

The answers are 31-b, 32-a, 33-d (Katzung, pp 4—7.) The absorption, distribution, and elimination of drugs require that they cross various cellular membranes The descriptions that are given in the question define the various transport mechanisms. The most common method by which ionic compounds of low molecular weight (100 to 200) enter cells is via membrane channels. The degree to which such filtration occurs varies from cell type to cell type because their pore sizes differ. 

Simple diffusion is another mechanism by which substances cross membranes without the active participation of components in the membranes. Generally, lipid-soluble substances employ this method to enter cells. Both simple diffusion and filtration are dominant factors in most drug absorption, distribution, and elimination. 

Wicklund, A., P. Runn, and L. Norrgren. 1988. Cadmium and zinc interactions in fish effects of zinc on the uptake, organ distribution, and elimination of 109Cd in the zebrafish, Brachydanio rerio. Arch. Environ. Contam. Toxicol. 17 345-354. 

Feroz, M. and M.A.Q. Khan. 1979a. Metabolism, tissue distribution, and elimination of cw-[14C] chlordane in the tropical freshwater fish Cichlasoma sp. Jour. Agric. Food Chem. 27 1190-1197. 

The pharmacokinetics of distribution and elimination of sodium valproate in mice and dogs has been reported by Schobben and van der Kleijn (12). 

Baker TS, Rickert DE. 1981. Dose-dependent uptake, distribution, and elimination of inhaled -hexane in the Fischer-344 rat. Toxicol Appl Pharmacol 61 (3) 414-422. 

Chu 1, Villeneuve DC, Becking GC, et al. 1980b. Tissue distribution and elimination of 2,8-dihydromirex in the rat. J Toxicol Environ Health 6 713-721. 

Chu I, Villeneuve DC, Viau A. 1982. Tissue distribution and elimination of photomirex in squirrel monkeys. Bull Environ Contam Toxicol 29(4) 434-439. 

With intraperitoneal administration, rats eliminated 28% of the original dose within 48 hours (Bull 1965), and mice eliminated 30 60% of the original dose within 96 hours (March et al. 1957). There appears to be insufficient toxicokinetic data to use as a basis for comparison of animals and humans. Additional studies comparing the rate and extent of absorption, distribution, and elimination in several different animal species after inhalation, oral, and dermal exposure to disulfoton could be useful. 

Polychlorinated biphenyls (PCBs) have been used in various industrial processes during the past 40 years but were not recognized as major environmental contaminants until 1966 (1). Fish as a major food source have attained the dubious honor of being the most frequently cited PCB contamination problem (2). In the following presentation disposition of PCBs in fish will be discussed from four points of view accumulation, metabolism, distribution and elimination. No attempt will be made to cover PCB residue levels found in fish in nature (3) or acute or chronic toxicity of PCBs in fish (4-20). 

Gakstatter, J.H. The uptake from water by several species of freshwater fish to p,p -DDT, dieldrin, and lindane their tissue distribution and elimination rate. PhD Dissertation, Univ. of North Carolina, Chapel Hill (1966)... 

Schultz, D. P., Harman, P. D. Uptake, distribution, and elimination of the lampricide 21,5-dichloro-41-nitrosalicyl-anilide (Bayer 73) by largemouth bass (Micropterus salmoides). J. Agrio. Food Chem. (In press)... 

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