Hydroxylated metabolites

A thin-layer chromatography assay was developed for ffie simultaneous determination of the three major hydroxylated metabolites of antipyrine 409,410, and 411 in urine of humans and other animals (82JPP168) (Scheme 95). 

Tricyclohexyltin hydroxide is metabolized in vivo to inorganic tin via di- and monocyclohexyltin derivatives (502), and in vitro studies suggested that the major, metabolic reaction is carbon-hydroxylation of the cyclohexyl group (503). Studies in vivo using either tri-phenyl[ Sn]tin acetate (467) or triphenyl[" Sn]tin chloride (504) in rats showed that these compounds are metabolized to yield substantial amounts of di- and monophenyltin derivatives, although no significant quantities of hydroxylated metabolites have been identified (503) in this case. 

Mepanipyrim in crop samples is recovered by acetone solvent extraction. The acetone is evaporated under reduced pressure and the residual aqueous extract is hydrolyzed with enzyme (jS-glucosidases) to release hydroxylated metabolite(s). After enzyme treatment, mepanipyrim and the propanol form metabolite are extracted with dichloromethane, purified by silica gel column chromatography and quantified by gas chromatography/nitrogen-phosphoms detection (GC/NPD). 

Fan, P. W. Zhang, F. Bolton, J. L. 4-Hydroxylated metabolites of the antiestrogens tamoxifen and toremifene are metabolized to unusually stable quinone methides. Chem. Res. Toxicol. 2000, 13, 45-52. 

Daunorubicin is an anthracycline that is sometimes referred to as an antitumor antibiotic. Daunorubicin inserts between base pairs of DNA to cause structural changes in DNA however, the primary mechanism of cytotoxicity is the inhibition of topoisomerase II. The pharmacokinetics are best described by a two-compartment model, with a terminal half-life of about 20 hours. The predominant route of elimination of daunorubicin and hydroxylated metabolites is hepatobiliary... 

In the case of deca-BDE, its suggested degradation process in mammals consists of a first reductive debromination where one, two or three bromine atoms can be replaced by hydrogen atoms followed by an oxidation to form hydroxylated metabolites, which are presumably formed from an intermediate epoxy [52]. This study detected traces of three nona-BDEs, which may be an indication of reductive debromination as a first step of degradation, and thirteen hydroxylated metabolites. Otherwise, the possibility of a deca-BDE oxidation as a first step to form the epoxy without an intermediate reductive debromination is also suggested [52]. The study conducted by Morck et al. [53] detected several hydroxylated products, from methoxy-hydroxy-pentabrominated to methoxy-hydroxy-heptabrominated compounds, which coincide with part of the metabolites obtained by Sandholm et al. [52]. In addition, both authors found that methoxy and hydroxy substituents are always on the same aromatic ring when both are present. Moreover,... 

Morck et al. [53] found traces of less brominated PBDEs than deca-BDE, indicating that the reductive debromination would be the first step in its degradation. In both articles, it is suggested the involvement of Cyp P450 in the oxidation reactions to form hydroxylated metabolites, but not in the reductive debromination proposed as the initial step. 

Regarding the reductive debromination as the first step of deca-BDE degradation in mammals, Huwe and Smith [54] detected the formation of different PBDEs (three nona-BDEs, four octa-BDEs and one hepta-BDE) from deca-BDE degradation in rats, which also suggests the existence of a reductive debromination process as the first step in deca-BDE degradation in mammals. In this case, it was not identified whether the specific enzymatic system responsible for the reductive debromination and the corresponding analyses to detect the formation of hydroxylated metabolites were not carried out. 

Moreover, considering the involvement of Cyp P450 in the first step of deca-BDE degradation by the fungus and previously reported for deca-BDE, BDE-154 and BDE-100 in mammals [50-53], it was expected that PBDE mixtures degradation products by the fungus would be very similar to those detected in degradation processes in mammals. These products correspond to hydroxylated and methoxy-hydroxylated metabolites. 

Figure 7.13 illustrates the utility of mass defect filtering (also known as exact mass filtering) and UPLC. It shows results of UPLC/MS assay of a bile sample containing buspirone and its metabolites.184 The top trace shows the (unfiltered) TIC for the sample the middle trace is the result of an exact mass filter the bottom trace is an extracted ion chromatogram for the M+16 or hydroxylated metabolites based on their exact masses. It is readily apparent that this new software tool may be very helpful for metabolite identification studies. 

Duffy JE, Hay ME (2001) The ecology and evolution of marine consumer-prey interactions. In Bertness MD, Gaines SD, Hay ME (eds) Marine community ecology. Sinauer, Sunderland, pp 131-158 Duisken M, Sandner F, Blomeke B, Hollender J (2005) Metabolism of 1,8-cineole by human cytochrome P450 enzymes identification of a new hydroxylated metabolite. Biochim Biophys Acta 1722 304-311... 

Hydroxylated metabolites are conjugated as glucuronides and sulfates. The balance of products in this last step and their distribution between urine and feces distinguishes the metabolism between humans, rats, and rabbits (Baldwin and Hutson 1980 Bedford et al. 1975b Hutson 1981 Hutson et al. 1975), as discussed in Section 2.3.4. Similarly, studies in lactating cows ingesting radio-labeled endrin in the diet for 21 days suggest metabolic pathways similar to those in rats and rabbits with apparent differences between the 3 species attributed more to differences in biliary versus renal excretion (Baldwin et al. 1976). 

An impressive list of degradative studies has been performed with Stauffer-s R-20458 including metabolism by eight insect species (15, 16), rats (15, 17), steers (18, 19), mice (20) and mammalian enzymes (15, 20, 21). It is evident that most published investigations have concentrated on metabolism by mammals and insects. Insect metabolism of R-20458 has been reviewed (22) and a summary of nonaquatic metabolism is given in Table V. Several additional hydroxylated metabolites were identified by Hoffman et al. (17) from rats. 

Henschler R, Glatt HR. 1995. Induction of cytochrome P4501A1 in haemopoietic stem cells by hydroxylated metabolites of benzene. Toxicol In Vitro 9 453-457. 

The biotransformation of clofexamide (4.33, Fig. 4.4), a compound with anti-inflammatory and antidepressant activities, was investigated in rats [18]. About 15% of the dose administered was found in urine as 2-(4-chlorophe-noxy)acetic acid (4.37). This metabolite was formed via the secondary amine 4.34, the primary amine 4.35, and the acid 4.36 resulting from oxidative deamination. However, direct formation of 2-(4-chlorophenoxy)acetic acid (4.37) from the parent compound (4.33) cannot be excluded. Clofexamide and its metabolite 4.34 also underwent hydroxylation on the aromatic ring, but these hydroxylated metabolites did not appear to be hydrolyzed. 

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