Tetracycline, oxidation

X = NH2, Y = H). Oxidation (54) of tetracyclines usiag the Udenfriend reagent has yielded 9-hydroxytetracyclines and disubstituted (C-7 and C-9) products (48) can also be obtained. Substituent assignments are made from nmr spectral iaterpretations. The 7- and 9-methyl tetracyclines have been prepared and reported to retain biological activity (55). 

The recent synthesis of (—)-tetracycline by Myers and co-workers incorporates a biocatalytic step in the first stage which oxidizes benzoic acid aerobically to an a,f)-dihydroxy derivative in the presence of a whole-cell mutant strain of Alcaligenes eutrophus. Figure 4.61 shows a reduced tree diagram for the synthesis and Table 4.28 summarizes the metrics parameters. 

Several classes of antibiotics, e.g., tetracyclines [86], fluoroquinolones [87, 88], and p-lactams [89] were observed to react with chemical oxidants such as chlorine dioxide (CIO2) and free chlorine. Oxidation with CIO2 yields hydroxylated and oxygenated products in the case of tetracyclines, and leads to dealkylation, hydroxylation, and intramolecular ring closure at the piperazine moiety of the fluoroquinolones [86, 88]. 

Reaction of these antibiotics with chlorine mostly generated chlorinated and OH-substituted by-products [86, 87]. Unlike fluroquinolones, whose quinolone ring is left mostly intact, disinfection with CIO2 may diminish the antibiotic capacity of tetracyclines because it leads to cleavage of the tetracyclines ring system [86,88]. On the other hand, oxidation of p-lactam antibiotics such as penicillin, amoxicillin, and cefadroxil with CIO2 leads to the formation of hydroquinone and a wide range of substituted phenols [89]. 

The sorption behaviour of antibiotics, in particular, can be very complex and therefore difficult to assess. As an example, ciprofloxacin has a log ATqw equal to 0.28, conferring it with a small tendency to leave the aquatic phase however, it does sorb well onto active sludge or sediments [62, 63] in WWTP. Tetracyclines (log A ow equal to 1.4), on the other hand, form complexes with double cations (calcium and magnesium) present in the water [64] and also tend to adsorb onto the surface of complexes between humic acids and hydrous Al oxide [65]. 

Magnesium Oxide (Mag-Ox 400, Others) [OTC] [Antacid, Magnesium Supplement/Magnesium Salt] Uses R lace low Mg levels Action Mg supl Dose 400-800 mg/d daily-qid w/ full glass of HjO Caution [B, +] Contra UlcCTative colitis, diverticulitis, ileostomy/colostomy, heart block, renal insuff Disp Caps 140 mg tabs 400 mg (OTC) SE D, N Inter actions X Effects OF chlordiaz oxide, dicumarol, digoxin, indomethacin, INH, quinolones, tetracyclines EMS Monitor ECG for hypokalemia (flattened T waves) OD Unlikely to cause life-threatening Sxs, but may cause D, constipation, cramps, and abd pain symptomatic and supportive... 

Fatty acid beta-oxidation Inhibition by valproate, tetracyclines, nonsteroidal antiinflammatory drugs, antianginal cationic amphiphilic drugs, female sex hormones, CoA depleters such as valproate and salicylate... 

Impairment of mitochondrial jj-oxidation leads to accumulation of fat, resulting in steatosis. Examples are various tetracycline derivatives, valproic acid (used to treat seizures) and overdoses of aspirin [64—66]. Certain NSAIDs such as ibuprofen, ketoprofen and naproxen also have the ability to inhibit jj-oxidation [67-69]. 

Labbe, G. et al. (1991) Effects of various tetracycline derivatives on in vitro and in vivo beta-oxidation of fatty acids, egress of triglycerides from the liver, accumulation of hepatic triglycerides, and mortality in mice. Biochemical Pharmacology, 41 (4), 638-641. 

Iron absorption occurs predominantly in the duodenum and upper jejunum. The physical state of iron entering the duodenum greatly influences its absorption. At physiological pH, ferrous iron is rapidly oxidized to the insoluble ferric form. Gastric acid lowers the pH in the proximal duodenum, enhancing the solubility and uptake of ferric iron. When gastric acid production is impaired, iron absorption is reduced substantially. Ascorbic acid enhances iron absorption. Ascorbic acid mobilizes iron from iron-binding proteins in vivo, which in turn could catalyze lipid peroxidation. Iron absorption is inhibited by antacids, phytates, phosphates and tetracyclines. 

Deprotection and oxidation of 12 gave 13, which was further oxidized to the sulfoxide. Elimination of the sulfoxide gave the naphthalene derivative 14, which underwent spontaneous oxidation to 15. Reductive deprotection then gave tetracycline 16. The diastereoselectivity of the air and light-mediated oxidation is remarkable. 

Titrations of TC-HC1 in non-aqueous medium are known. TC-HC1 is dissolved in glacial acetic acid, 6% mercuric acetate solution added and then titrated potentiometrically with 0.1 N perchloric acid in dioxane (96, 97, 98). Indirect volumetric determination of TC-HC1 after formation of a tetracycline -thiocyano-chrom (III)-complex through oxidation with KMn04, KBrC>3 and KIO3 has also been reported (99). 

Phototoxicity occurs when skin exposed to sunlight, especially in the UVA region of 320 to 400 nm, reddens and develops blisters as a consequence of the presence of certain chemical species. The phototoxic chemical species that result in such reactions are ones to which an individual is exposed either directly on the skin or systemically. These compounds absorb ultraviolet radiation and, like the porphyrins discussed above, enter excited states interacting with 02 to generate destructive oxidant species and free radicals. Numerous chemical species, including furocoumarins, polycyclic aromatic hydrocarbons, tetracyclines, and sulfonamides, can be phototoxic. 

Chemical instability reactions appear with or without microbiological contribution through reactions such as hydrolysis, oxidation, isomerization, and epi-merization. Interactions between ingredients and ingredients with container closure materials are established as the principal causes of these reactions [1], for instance, the hydrolysis of cefotaxime sodium, the oxidation of vitamin C, the isomerization of epinephrine, and the epimerization of tetracycline [7],... 

There are several drugs that inhibit beta oxidation of fatty acids in mitochondria leading to lipid accumulation, such as aspirin, valproic acid, and tetracyclines. 

Enzymatic Inactivation (e.g.. Hydrolysis) Covalent Modification Oxidation/Reduction P-Lactams, Fosfomycin Aminoglycosides, Chloramphenicol Tetracycline... 

Moore DE, Fallon MP, Burt CD. Photo-oxidation of tetracycline—a differential pulse polarographic study. Int J Pharm 1983 14 133-142. 

Wiebe JA, Moore DE. Oxidation photosensitized by tetracyclines. J Pharm Sci 1977 66 188-189. 

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