Tetracyclines metabolites

As indicated, the ionized form of a drug will be more soluble than the nonionized form in the aqueous fluids of the GIT. The classic studies on the beneficial effects of changing nonionized drugs into salt forms were reported by Nelson for tetracycline [25], and Nelson et al. for tolbutamide [26]. Table 2 combines portions of the data from each study. Urinary excretion of the drug or its metabolite was taken as the in vivo measure of the relative absorption rate for the salt and the nonionized... 

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). 

CZE is the most widely used mode due to its simplicity of operation and its versatility. Selectivity can be most readily altered through changes in running buffer pH or by use of buffer additives such as surfactants or chiral selectors. The major drawback with CZE is that it deals with aqueous electrolytic systems, whereas components can only be separated if they are charged and soluble in water. CZE separation of various antibacterials including penicillins, tetracyclines, and macrolides has been reported (86). Determination of cefixime, an oral cephalosporin antibiotic, and its metabolites in human urine has been also successfully carried out with CZE (87). 

The applicability of the APCI interface is restricted to the analysis of compounds with lower polarity and lower molecular mass compared with ESP and ISP. An early demonstration of the potential of the APCI interface is the LC-APCI-MS-MS analysis of phenylbutazone and two of its metabolites in plasma and urine (128). Other applications include the LC-APCI-MS analysis of steroids in equine and human urine and plasma (129-131), the determination of six sulfonamides in milk samples after a simple solid-phase extraction and LC separation (132), of tetracyclines in muscle at the 100 ppb level (133), of fenbendazole, oxfendazole, and the sulfone metabolite in muscle at the 10 ppb level, and of five thyreostats in thyroid tissue at the 1 ppm level (134). 

Inhibitors are substances that tend to decrease the rate of an enzyme-catalysed reaction. Although some act on the substrate, the discussion here will be restricted to those inhibitors which combine directly with the enzyme. Inhibitors have many uses, not only in the determination of the characteristics of enzymes, but also in aiding research into metabolic pathways where an inhibited enzyme will allow metabolites to build up so that they are present in detectable levels. Another important use is in the control of infection where drugs such as sulphanilamides competitively inhibit the synthesis of tetrahydrofolates which are vitamins essential to the growth of some bacteria. Many antibiotics are inhibitors of bacterial protein synthesis (e.g. tetracyclin) and cell-wall synthesis (e.g. penicillin). 

Secondary metabolism is commonly achieved by uncoupling the anabolic from the growth pathways. The subsequent overflow metabolites are then channelled towards secondary products which may include such antibiotics as penicillin, tetracyclin and streptomycin. Figure 5.16 shows the relationship between secondary products and central anabolic pathways. 

A multiresidue procedure using LC fractionation for the identification and determination of 14 penicillins and cephalosporins and their metabolites in milk and tissue samples was presented (72). This procedure completed the previously published papers for the analysis of selected /3-lactam residues in milk and tissue samples and gave an excellent tool for the determination of most antibiotic groups except for the tetracyclines. 

Fate All the tetracyclines concentrate in the liver, where they are, in part, metabolized and conjugated to form soluble glucuronides. The parent drug and/or its metabolites are secreted into the bile most tetracyclines are reabsorbed in the intestine and enter the urine by glomerular filtration. Doxycycline is an exception, since its metabolite is preferentially excreted via the bile into the feces. Thus, unlike other tetracyclines, doxycycline can be employed in treating infections in renally compromised patients. 

In a retrospective review of drug safety databases, minocychne was the only tetracychne derivative that caused drug-induced lupus (SEDA-22, 268) (38). The authors proposed that the propensity of minocycline to cause drug-induced lupus may be due to the presence of a functional group that is easily oxidized to a reactive metabolite. However, the chemicaUy modified tetracycline CMT-3, which has also reportedly caused a lupus-like syndrome (39), lacks this group, so another theory is needed. 

The applicability of the APCI interface is restricted to the analysis of compounds with lower polarity and lower molecular mass, compared with ESP and ISP. Applications include the LC-APCI-MS multiresidue determination of quinolone antibiotics, the determination of tetracyclines in muscle at the 100-ppb level,and the determination of fenbendazole, oxfendazole, and the sulfone metabolite in muscle at the 10-ppb level. 

LC/MS has had a strong influence upon pharmaceutical chemistry for the analysis of both highly polar metabolites and their precursors, as described in the second section of this book. The technique has been used for the analysis of polypeptides and a variety of intractable pharmaceuticals such as tetracycline, -lactams, and polyether antibiotics. The structures of highly polar drug metabolites formed in vivo— including sulfate esters, glucuronides, taurine, and camotine... 

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