Excretion of xenobiotics

Hirom [71,72] demonstrated more than three decades ago that the route of excretion of xenobiotics is dependent upon MW by testing up to 75 compounds in rat, guinea-pigs, and rabbits. Lower MW compounds (< 350) were mainly eliminated in the urine (>90%). As MW increased from 350 to 450, a sharp increase in the fraction of compound eliminated in the bile occurred, and for MW > 450, compounds were eliminated 50-100% in the bile in all three species. Smith [73] correlated the log of free metabolic and renal clearance (ml/min/kg) with log D, and found a similar relationship. Metabolic clearance increases with increasing log D, while renal clearance decreases with increasing log D. 

The detoxification and excretion of xenobiotics (i.e., foreign compounds, including diet-derived allelochemicals) involve a suite of highly complex processes that allow an organism to respond to its internal and external chemical environments. Suchmetabolic resistance involves the biochemical transformation... 

Curtis LR, Mehendale HM. 1979.The effects of Kepone treatment on biliary excretion of xenobiotics in the male rat. Toxicol Appl Pharmacol 47 295-303. 

Metabolites are generated by the body s own biochemical processes as a way to facilitate excretion of xenobiotics. The enzymes catalysing in vivo modification of drugs and druglike molecules have a fundamental significance for the pharmaceutical industry. This was once primarily the field of the pharmacologist, but interest in metabolic reactions... 

It is necessary to appreciate both for a mechanistic view of toxicology. The first of these includes the absorption, distribution, metabolism, and excretion of xenobiotics, which are all factors of importance in the toxic process and which have a biochemical basis in many instances. The mode of action of toxic compounds in the interaction with cellular components, and at the molecular level with structural proteins and other macromolecules, enzymes, and receptors, and the types of toxic response produced are included in the second category of interaction. However, a biological system is a dynamic one, and therefore a series of events may follow the initial response. For instance, a toxic compound may cause liver or kidney damage and thereby limit its own metabolism or excretion. 

These protein transporters are clearly important in the absorption, distribution, and excretion of xenobiotics. There are many other transporters, which may play a role at times in xenobiotic toxicity and detoxication. 

Melegh B, Kerner J, Jaszai V, Bieber L. Differential excretion of xenobiotic acylesters of carnitine due to administration of pivampicillin and valproate. Biochem Med Metabol Biol 1990 43 30-8. 

Yamazaki M, Suzuki H, Sugiyama Y. Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics. Pharm Res 1996 13(4) 497-513. 

Canaliculi enter canals of Hering in the portal triad and lead to intrahepatic bile ducts which coalesce to form the hepatic bile duct. The bile duct empties the bile into the gaU bladder which then is released into the duodenum. Bile that is excreted into the small intestine enhances nutrient uptake, protects enterocytes from oxidation, and facilitates excretion of xenobiotics and endogenous waste in the feces (Treinen-Moslen, 2001). 

The pKa is an important physicochemical parameter. The analyte pKa values are especially important in regard to pharmacokinetics (ADME—absorption, distribution, metabolism, excretion) of xenobiotics since the pKa affects the apparent drug lipophilicity [59]. Potentiometric titrations and spectrophome-tric analysis can be used for pKa determination however, if the compound is not pure, is poorly soluble in water, and/or does not have a significant UV chromophore and is in limited quantity, its determination may prove to be challenging. 

Pharmacokinetics/toxicokinetics is the area of toxicology that is concerned with the role of absorption, distribution, metabolism, and excretion of toxicants in the body. These events, some of which may be interdependent, often have a very significant impact on the toxicity of a chemical in a specific species. Quantitative characterization of the time profile of absorption, distribution, metabolism, and excretion of xenobiotic compounds is included in the area of pharmacokinetics. In this sense, pharmacokinetics is used synonymously with toxicokinetics. 

Carver, M.P. Riviere, J.E. (1989) Percutaneous absorption and excretion of xenobiotics after topical and intravenous administration to pigs. Fundamental and Applied Toxicology, 13, 714-722. 

When toxic exposures are repeated, the timing as well as the dosage of the exposures is critical. The metabolism and excretion of xenobiotics proceed at finite rates. Stated another way, time is needed for the body to rid itself of the absorbed chemical and its metabolites. Let us consider a situation where the first exposure is at a level that the body can readily metabolize and excrete. If a second toxic exposure to the same chemical at the same level occurs before the body has had sufficient time to cleanse itself, a toxic buildup will occur with the onset of symptoms. 

I am grateful to J. B. Pritchard for stqiplying unpublished results, and for continued stimulating discussion on the role of metabolism in excretion of xenobiotics. 

Fleck, C. and Braunlich, H. Factors determining the relationship between renal and hepatic excretion of xenobiotics. Arzneim.-Forsch. 40 942—946, 1990. 

The liver excretes many drugs and other foreign chemicals into bile, but little is known about efficient ways to enhance biliary excretion of xenobiotics for the treatment of acute poisoning. Inducers of microsomal enzyme activity enhance biliary excretion of some xenobiotics, but the effect is slow in onset. 

Plants that increase bile production (artichoke, turmeric) actually speed up the excretion of xenobiotics, and help detoxification. There is no evidence to prove that this effect wonld improve the general health of anyone—unless they suffer from... 

A. I Central role of the liver. The role of the liver in the excretion of xenobiotics exposes it to high concentrations of toxicants and their metabolites. 

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