5- epi-Tetracycline

All samples contained the metabolite 4-epi-tetracycline, and this was even more pronounced in the liquid manure. Under strong acidic conditions (pH < 2), tetracycline is metabolized to anhydro-tetracyclines, which are bioactive, whereas alkaline pH conditions (pH > 7.5) can favor the formation of isotetracyclines, which show almost no in vitro activity. Tetracycline can also undergo extensive photodecomposition, forming a variety of products (Oka et al., 1989 Peterson et al., 1993). 

Due to their extremely polar character, tetracyclines bind with proteins to form conjugates that are difficult to extract from biological matrices. Use of dilute mineral acids is of great help in dissociating tetracyclines from proteins, but once in aqueous solution, their exfraction into volatile organic solvents for further concentration and cleanup is hampered by the unfavorable partition coefficients. Most of these antibiotics are photosensitive compounds, whereas all of them show poor stability under strong acidic and alkaline conditions with reversible formation of the 4-epi-tetracyclines in weakly acidic conditions (pH 3), and anhydro-tetracyclines in strong acidic conditions (below pH 2). 

In acidic conditions the tetracyclines undergo epimerisation at carbon atom 4 to form an equilibrium mixture of tetracycline and the epimer, 4-epi-tetracycline (Scheme 4.7). The 4-epi-tetracycline is toxic and its content in medicines is restricted to not more than 3%. The epimerisation follows the kinetics of a first-order reversible reaction (see equation (4.24)). The degradation rate is pH-dependent (maximum epimerisation occurring... 

Tetracyclines Tetracyclines are broad spectrum antibiotics obtained from Streptomyces strains or prepared semisynthetically. Use of tetracyclines has resulted in three types of renal effects. First, the use of outdated tetracyclines results in direct proximal tubular toxicity characterized by the increased excretion of amino acids, glucose, and phosphate (Fan-coni syndrome). The mechanism of this response is unclear, but appears to be due to the formation of the degradation product anhydro-4-epi-tetracycline. Second, administration of some tetracyclines, particularly demeclocycline, can result in a dose-dependent, reversible nephrogenic diabetes insipidus, which appears to result from an inhibition of ADH effects on water reabsorption. Lastly, in patients with preexisting compromised renal function, tetracyclines can induce increased sodium excretion and azotemia. The mechanism of the naturesis may be due to an effect of tetracyclines on luminal membrane sodium conductance, while the azotemia appears to result from the antianabolic effects of the tetracyclines. 

Efforts have been made to correlate electronic stmcture and biological activity in the tetracycline series (60,61). In both cases, the predicted activities are of the same order as observed in vitro with some exceptions. The most serious drawback to these calculations is the lack of carryover to in vivo antibacterial activity. Attempts have also been made (62) to correlate partition coefficients and antibacterial activity. The stereochemical requirements are somewhat better defined. Thus 4-epitetracycline and 5a-epitetracycline [65517-29-5] C22H24N20g, are inactive (63). The 6-epi compound [19369-52-9] is about one-half as active as the 6a (or natural) configuration. 

The unexpected biological activities of tetracyclines, such as 5a-epi-6-epitetracychne [19543-88-5] C22H24N20g, and 7-chloro-5a,lla-dehydro-6-epitetracycline [22688-60-4] C22H22ClN20g, make predicting stmcture-activity relationships difficult (64). Aside from the C-2 amide Mannich-base derivatives, variation at other centers in the molecule, ie, C-4, 4a, 5a, 12a, decreases the biological activity. 

Oxytetracycline (OTQ and oxytetracycline hydrochloride (OTC HC1) may contain the impurities 4-epi-oxytetracycline (EOTC), tetracycline (TC) and 2-acetyl-2-dec-arboxamido-oxytetracycline (ADOTQ [2,4]. According to European Pharmacopoeia, oxytetracycline hydrochloride may also contain anhydro-oxytetracycline (AOTQ, a-apo-oxytetracycline (a-AOTC), /i-apo-oxytetracyclinc (/FA OTC). The structures are shown in Fig. 1. 

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],... 

Another instability leading to a dramatic decrease of antibacterial action, to which all clinically used tetracyclines are subject, is epimerization of the natural 4-a-dimethy-lamino group A to the p-epimer B (Eq. 6.11). Under acidic conditions a 1 2 equilibrium is established in solution within a day. This occurs in a variety of solvents, especially acetic acid. Anions also tend to support this process. Divalent ions that chelate tetracyclines, particularly Ca2+, facilitate the reversal of the epimerization from the epi to the natural isomer. 

Tetracycline, 4-epitetra-cycline, chlortetracycline, epi-anhydrotetracycline, and anhydrotetracycline Ion-pair chromatography Microparticulate silica whose surface silanol sites had been fully silanized. Parchloric acid/ acetonitrile... 

Muhammad, N. Bodnar, J.A. Separation and quantitation of chlortetracycline, 4-epitetracycline, 4-epi-anhydrotetracycline, and anhydrotetracycline in tetracycline by high-performance liquid chromatography. J.Pharm.Sci., 1980, 69, 928-930... 

Chopra I, Roberts M Tetracycline antibiotics Mode of action, applications, molecular biology, and epi-... 

From starting line iso-tetracycline, epi-tetra-cycline, epi-chlortetracycline, iso-chlortetracyc-line, tetracycline, hydroxytetracycline, demethylchlortetracycline, chlortetracycline, anhydrotetracycline, anhydrochlortetracycline Ref. 

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