Biotransformation tissue distribution

Coldham, N.G., S. Sivapathasundaram, M. Dave, L.A. Ashfield, T.G. Pottinger, C. Goodall and M.J. Sauer. Biotransformation, tissue distribution, and persistence of 4-nonylphenol residues in juvenile rainbow trout (Oncorhynchus mykiss). Drug Metab. Dispos. 26 347-354, 1998. 

Generic chemical class data are often relevant to assessing potential toxicity and should be a part of any evaluation. The relevant information includes structure-activity relationships and physical-chemical properties, such as melting point, boiling point, solubility, and octanol-water partition coefficient. Physical-chemical properties affect an agent s absorption, tissue distribution, biotransformation, and degradation in the body. 

It is also good to realize that properties like fragment lipophilicity contributions are additive properties, but may be very much dependent on the structural environment (Fig. 22.5). Some substitutions may have a more dramatic effect than expected. Radioactive labelling with I is quite common for biological studies. One should be aware, however, that aromatic iodination increases the log P of the compound by approximately 1 log P unit, and thus a different tissue distribution may result. An aromatic fluoro substituent has very little effect on the lipophilicity, but mainly serves in drugs to avoid oxydative biotransformation. 

Tissue Distribution and Biotransformations. After entering the blood, tin is found in the kidney, liver, brain, and adipose tissue [29] as a consequence of the lipophilic properties of organotins. 

Prout M, Howard E, Soames A (1985a) PP993 Absorption, excretion and tissue distribution of a single oral dose (1 mg/kg) in the rat. Syngenta unpublished report, no. CTL/P/1064, UK. Prout M, Gibson N, Howard E (1986) PP993 Biotransformation in the rat. Syngenta unpublished report, no. CTL/P/1295, UK. 

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. 

After absorption, OC compounds are rapidly distributed and accumulate in high-fat-content tissues the degree of accumulation is inversely related to the rate of biotransformation into water-soluble metabolites. The biological half-lives range from a minimum value of 24 hr for lindane, to 1 year for dieldrin, to 3-4 years for DDT (Tordoir and Van Sittert, 1994). 

Dispositional antagonism occurs when one drug alters the pharmacokinetics (absorption, distribution, biotransformation, or excretion) of a second drug so that less of the active compound reaches the target tissue. Tor example, phenobarbital induces the biotransformation of warfarin, reducing its anticoagulant activity... 

When levels of the drug decline in plasma, usually due to biotransformation and excretion, the drug then redistributes away from its site of action into other tissues (e.g., drugs may distribute across the placenta during pregnancy). This is a passive process, but lipid-soluble drugs penetrate the most. 

Pharmacokinetics is defined as the study of the quantitative relationship between administered doses of a drug and the observed plasma/blood or tissue concentrations. The field of pharmacokinetics is concerned with drug absorption, distribution, biotransformation, and excretion or elimination. These processes, in addition to the dose, determine the concentration of drug at the effector or active site and, therefore, the intensity and duration of drug effect. 

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