Biologically active metabolite

Desogestrel. Desogestrel (44) is rapidly and nearly completely converted to the biologically active metabolite 3-ketodesogestrel [14048-10-1]... 

If, for example, the route from parent carcinogen to the actual biologically-active metabolite is considered as a multi-step pathway, the terms that appear in the model equation can be thought of as representing the rate-determining steps. 

The reaction of metabolically generated polycyclic aromatic diol epoxides with DNA Ua vivo is believed to be an important and critical event in chemical carcinogenesis Cl,2). In recent years, much attention has been devoted to studies of diol epoxide-nucleic acid interactions in aqueous model systems. The most widely studied reactive intermediate is benzo(a)pyrene-7,8-diol-9,10-epoxide (BaPDE), which is the ultimate biologically active metabolite of the well known and ubiquitous environmental pollutant benzo(a)pyrene. There are four different stereoisomers of BaPDE (Figure 1) which are characterized by differences in biological activities, and reactivities with DNA (2-4). In this review, emphasis is placed on studies of reaction mechanisms of BPDE and related compounds with DNA, and the structures of the adducts formed. 

W. Hammer, B. Holmstedt, B. Karlen, F. Sjoqvist, J. Vesman, The Metabolism of Trem-orine. Identification of a New Biologically Active Metabolite, V-(4-Pyrrolidino-2-2-bu-ynyl)-y-aminobutyric Acid , Biochem. Pharmacol. 1968,17, 1931-1941. 

Krohn K et at. Biologically active metabolites from fungi. Patt 16 New preussomerins J, K and L from an endophytic fungus Sttuctute elucidation, crystal structure analysis and determination of absolute configutation by CD calculations, Tetrahedron 57 4343—4348, 2001. 

As for the cultivation of other types of marine microorganisms, e.g., those with a specific potential for the production of biologically active metabolites, predominantly small-scale experiments (shake flasks) have been described. Alternatively, artificial seawater or 25 50 75 90% natural seawater has served as a basis for nutrient media. The concentrations of carbon and nitrogen sources reached up to 2 % (w/w) starch, glucose, molasses, glycerol, soybean oil, yeast extract, malt extract, beef extract, peptone, cornsteep liquor and NZ-amine. In the absence of artificial or natural seawater, high concentrations of... 

Discontinuation of a hypnotic after a month of continued use can cause a rebound of REM (rapid eye movement) sleep. The duration of action of a hypnotic is determined not only by the half-life of the mother substance but especially by their biological half-life determined by the half-life of the mother substance and the biological active metabolites. On this basis the benzodiazepines can be divided in four different groups ultra short-acting with a half-life < 6 hours such as midazolam and triazolam, short-acting with half-lives between 6 and 12 hours like lormetazepam, loprazolam, oxazepam and temazepam. Alprazolam, bromazepam... 

Diphenoxylate (marketed in combination with atropine as Lomotil in the United States) is chemically related to both analgesic and anticholinergic compounds. It is as effective in the treatment of diarrhea as the opium derivatives, and at the doses usually employed, it has a low incidence of central opioid actions. Diphenoxylate is rapidly metabolized by ester hydrolysis to the biologically active metabolite difenoxylic acid. Lomotil is recommended as adjunctive therapy in the management of diarrhea. It is contraindicated in children under 2 years old and in patients with obstructive jaundice. Adverse reactions often caused by the atropine in the preparation include anorexia, nausea, pruritus, dizziness, and numbness of the extremities. 

Vitamin D3 is transported to liver where it undergoes a hydroxylation at C-25 into 1a,25-dihydroxyvitamin D3 (calcitriol) (Fig. 64). In the kidney, it undergoes further hydroxylations at different sites, depending on the serum Ca + concentration. The most biologically active metabolite of vitamin D3 is calcitriol, which plays important roles in the regulation of calcium and phosphorus metabolism. It is used for treating bone diseases, but is also involved in the cell proliferation and the inducement of cell differentiation [151]. 

This lack of information may well relate to bupropion s complex metabolism, whereby biologically active metabolites predominate several-fold over the parent compound these metabolites may ultimately prove to be the basis for therapeutic effects [Golden et al. 1988]. Furthermore, because the full spectrum of action of the metabolites has not been explored, it is difficult to confidently characterize the primary biochemical action of bupropion as noradrenergic. One must therefore be cautious in interpreting any distinct aspects of bupropion s clinical actions as reflecting some noradrenergic mechanisms. And to our knowledge, bupropion is unique in that no other compound available for use in humans has a similar overall profile of preclini-cal and clinical biochemical effects. 

After oral administration it is bound to plasma proteins and it is metabolised to biologically active metabolite. 

Azathioprine is a cytotoxic inhibitor of purine synthesis effective for the control of tissue rejection in organ transplantation. It is also used in the treatment of autoimmune diseases. Its biologically active metabolite, mercaptopurine, is an inhibitor of DNA synthesis. Mercaptopurine undergoes further metabolism to the active antitumour and immunosuppressive thioinosinic acid. This inhibits the conversion of purines to the corresponding phosphoribosyl-5 phosphates and hypoxanthine to inosinic acid, leading to inhibition of cell division and this is the mechanism of the immunosuppression by azathioprine and mercaptopurine. Humans are more sensitive than other species to the toxic effects of the thiopurines, in particular those involving the haematopoietic system. The major limiting toxicity of the thiopurines is bone marrow suppression, with leucopenia and thrombocytopenia. Liver toxicity is another common toxic effect. 

Vitamin D is a prohormone that serves as precursor to a number of biologically active metabolites (Figure 42-3). Vitamin D is first hydroxylated in the liver to form 25-hydroxyvitamin D (25[OH]D). This metabolite is further converted in the kidney to a number of other forms, the best studied of which are 1,25-dihydroxyvitamin D (l,25[OH]2D) and 24,25-dihydroxyvitamin D (24,25[OH]2D). Of the natural metabolites, only vitamin D and l,25(OH)2D (as calcitriol) are available for clinical use (Table 42-1). Moreover, a number of analogs of l,25(OH)2D are being synthesized to extend the... 

Duckworth, A. and Battershill, C. (2003). Sponge aquaculture for the production of biologically active metabolites The influence of farming protocols and environment. Aquaculture 221, 311-329. 

Clarithromycin inhibits CYP3A4, which is responsible for the metabolic clearance of prednisolone, the biologically active metabolite of prednisone. Clarithromycin (500 mg bd for 2 days) reduced the clearance of methylpredniso-lone by 65% and significantly increased its plasma concentrations clarithromycin did not influence the clearance or plasma concentrations of prednisone (488). Acute mania has been reported to be related to inhibition of the metabolic clearance of prednisone by clarithromycin (SEDA-22, 444 489). 

Duckworth A, Battershill C (2003) Sponge Aquaculture for the Production of Biologically Active Metabolites The Influence of Farming Protocols and Environment. Aquaculture 221 311... 

Su JY, Zeng FM, Zhong YL, Fu X (1995) Biologically-Active Metabolites from Marine Organisms. J Chin Chem Soc 42 735... 

The biological methods are popular for three reasons 1) in most biological samples the concentration of vitamin D3 is very low and is not suitable for more specific methods because of interfering materials even after extensive cleanup 2) vitamin D3 is effective biologically in trace amounts making it more sensitive than the best chemical methods and 3) the biological methods are specific for vitamin D3 and its biologically active metabolites. The chief... 

Lund and DeLuca (101) administered [ H] vitamin D3 to rats and found biologically active metabolites in the bone, liver and serum. The aqueous-soluble metabolites from the tissues and the feces did not have vitamin D activity. At least three biologically active metabolites were isolated from the chloroform-soluble portion of the extract. One of these was found in large amounts in the liver, blood and bone. In 1968, Blunt et. al. (102) proved convincingly that this major metabolite is 25-hydroxyvitamin D3 (25-OH-D3). Two other groups of investigators (103,104) independently found clues to the metabolic hydroxylation of vitamin Do. It was soon established that 25-hydroxylation of vitamin D3 takes place primarily in the liver (105,106) and that 25-0H-D3 is the major form of circulating vitamin D3 in human plasma (107). 

Initially, 25-OH-D3 was considered to be the main biologically active metabolite of vitamin D. But soon it was discovered that physiological concentrations of 25-0H-D3, like vitamin D3, are incapable of stimulating either intestinal calcium transport or bone calcium jnobilization (108-110). Earlier work (111,112) with [la- H] vitamin D3 had shown that one of the unknown metabolites had lost its tritium from the C-l position. Fraser and Kodicek (113) established that this active metabolite is 1-oxygenated 25-OH-D3 and that it was produced in the kidney. A short time later Lawson et al. (114) identified this metabolite to be la, 25-dihydroxyvitamin D3 (1,25-(0H)2D3) which was confirmed by other investigators (115,116). 

AB Rifkind Cornell University Medical Center, Ithaca, NY Use a chick embryo model to investigate whether 2,3,7,8-TCDD-induced P-450 participates in 2,3,7,8-TCDD toxicity by metabolizing endogenous compounds, such as the membrane fatty acid, arachidonic acid (AA), to biologically active metabolites that can affect cell signals and thereby modulate toxicity ... 

Thompson, J. E., Exudation of biologically-active metabolites in the sponge Aplysina fistularis. I. Biological evidence, Mar. Biol., 88, 23, 1985. 

Battershill, C. N., Pomponi, S. A., Willoughby, R., Northcote, L., McClean M. L., Munro, M. H. G., Blunt, J. W., and Garson, M. J., Sponge cells or symbionts The site of biosynthesis of biologically active metabolites in two species of sponges and the feasibility of cell culture as a production option, in 9th International Symposium on Marine Natural Products, 1998, Symposium Proc., Tonnville, Australia. 

Morphine is known to be metabolized by glucuronidation to two biologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) (Boemer et al., 1975). M6G has high affinity for the /(-opioid receptor (Loser et al., 1996 Pasternak et al., 1987 Paul et al., 1989) and appears to be a more potent opioid agonist than morphine (Frances et al., 1992 Osborne el al., 2000 Pasternak et al., 1987 Paul el al., 1989). In contrast, M3G does not bind to ji-, 6-, or K-opioid receptors (Loser et al., 1996 Pasternak et al., 1987) and appears to be devoid of analgesic activity (Pasternak et al., 1987 Yaksh and Harty, 1988). 

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