Excretion and Degradation

The disappearance of alkaloids from plant tissue has been attributed to leaching (301-303), migration, excretion, or physiological degradation. The loss of volatile alkaloids (nicotine) by exhalation was observed by Ciamician and Ravenna (304) and by Chaze (305), who showed that nicotine can penetrate the epidermis (306). The loss of Ephedra alkaloids during the rainy season may be partly due to leaching (307). Isolated roots of Nicotiana, Atropa, and others excrete considerable amounts of alkaloid into the medium, but roots of intact plants excrete very little. 

---

DON can often be the largest pool of dissolved combined N but it is largely uncharacterized (see Chapter 3 by Aluwihare and Meador, this volume Bronk, 2002). The marine DON pool consists of highly reactive and relatively recalcitrant fractions and, while largely uncharacterized, includes a variety of compounds such as urea, dissolved free and combined amino acids and a variety of cellular intermediates, and excretion and degradation products that can be readily taken up (Table 7.1) and metabolized by phytoplankton and bacteria in the environment. Unfortunately, rates of DON uptake (excluding urea) are rarely measured. 

Fasting plasma insulin is therefore increased owing not only to peripheral resistance to its action but also to decreased renal excretion and degradation by skeletal muscle (Rl). Plasma levels of proinsulin and C-peptide, both excreted by the kidney, are also increased. Glucagon (3500 Da) and its larger precursor (9000 Da) are also increased because of reduced degradation (M36). Hyperglucago-nemia is corrected by renal transplantation but not by dialysis. 

It would be particularly desirable to produce nalline with a radioactive allyl group. Then studies should be made, with standard chemical and radioactivity techniques, of rates of excretion and degradation of nalline and morphine (radioactive methyl group) and the alterations in excretion and degradation of morphine when nalline is administered. The possibility of tracing either the nalline or the morphine separately should yield valuable information on the mechanism of action of both morphine and nalline. 

Pittman, K.A., Goldberg, L. Coulston, F. (1976) Carrageenan the effect of molecular weight and polymer type on its uptake, excretion and degradation in animals. Food Cosmet. Toxicol. 14(2), 85-93. 

From the above it will be apparent that the physico-chemical properties of a potential agent must be very finely adjusted if it is to avoid the many casualties of storage, excretion, and degradation. In many cases, by accident or by design, substances have been obtained with properties favourable for their accumulation near an appropriate receptor then, if their chemical structure is complementary to that of the receptor, the desired biological action takes place. 

Wilson, J. D., 1964, The quantification of cholesterol excretion and degradation in the isot-pic steady state in the rat The influence of dietary cholesterol, J. Lipid Res. 5 409. 

Several approaches have been made towards quantification of the cholesterol steady state in the rat. Chevallier (1956) described the turnover rate of cholesterol in most tissues and calculated the amount of replaceable cholesterol present in each. He found (Chevallier, 1960) that the cholesterol synthesized by the intestinal wall does not equilibrate with the blood cholesterol. These findings are at variance with those arising from the ingenious experiments of Wilson (1964), who attempted to quantitate cholesterol excretion and degradation in the rat and found that the major portion of fecal cholesterol of endogenous origin is derived from or is in equilibrium with the blood. Both Chevallier and Wilson used isotopically labeled cholesterol administered orally, intravenously or by implantation. 

Sandvig, K., Olsnes, S., 1979. Effect of temperature on the uptake, excretion and degradation of abrin and ricin by HeLa cells. Exp. Cell Res. 121,15-25. 

Ammonia (NH3) is just one of the toxins implicated in HE. It is a metabolic by-product of protein catabolism and is also generated by bacteria in the GI tract. In a normally functioning liver, hepatocytes take up ammonia and degrade it to form urea, which is then renally excreted. In patients with cirrhosis, the conversion of ammonia to urea is retarded and ammonia accumulates, resulting in encephalopathy. This decrease in urea formation is manifest on laboratory assessment as decreased blood urea nitrogen (BUN), but BUN levels do not correlate with degree of HE. Patients with HE commonly have elevated serum ammonia concentrations, but the levels do not correlate well with the degree of central nervous system impairment.20... 

In the above-mentioned examples, the prediction of CYP-mediated compound interactions is a starting point in any metabolic pathway prediction or enzyme inactivation. This chapter presents an evolution of a standard method [1], widely used in pharmaceutical research in the early-ADMET (absorption, distribution, metabolism, excretion and toxicity) field, which provides information on the biotransformations produced by CYP-mediated substrate interactions. The methodology can be applied automatically to all the cytochromes whose 3 D structure can be modeled or is known, including plants as well as phase II enzymes. It can be used by chemists to detect molecular positions that should be protected to avoid metabolic degradation, or to check the suitability of a new scaffold or prodrug. The fully automated procedure is also a valuable new tool in early-ADMET where metabolite- or mechanism based inhibition (MBI) must be evaluated as early as possible. 

Biosynthesis of endogenous compounds and storage, conversion, and degradation of them into excretable molecules (metabolism). In particular, the liver is responsible for the biosynthesis and degradation of almost all plasma proteins. 

The kidneys main function is excretion of water and water-soluble substances (1). This is closely associated with their role in regulating the body s electrolyte and acid-base balance (homeostasis, 2 see pp.326 and 328). Both excretion and homeostasis are subject to hormonal control. The kidneys are also involved in synthesizing several hormones (3 see p. 315). Finally, the kidneys also play a role in the intermediary metabolism (4), particularly in amino acid degradation and gluconeo-genesis (see p. 154). 

Busulfan (Myleran) is a bifunctional methanesulfonic ester that forms intrastrand cross-linkages with DNA. The drug is well absorbed after oral administration and has a plasma half-life of less than 5 minutes. Metabolites and degradation products are excreted primarily in the urine. 

It must be biocompatible and degradable (i.e., it should degrade in vivo into smaller fragments, which can then be excreted from the body). 

---