Hydroxy metabolite

Figure 5.46 Product-ion spectra of (a) Bosentan (1) [M -F H] 552.1917, and its (b) hydroxy metabolite (2) [M + H]+ 568.1866, (c) phenol metabolite (3) [M + H] 538.1760, and (d) hydroxyphenol metabolite (4) [M-FH] 554.1790. Reprinted by permission of Elsevier Science from Exact mass measurement of product ions for the structural elucidation of drug metabolites with a tandem quadrupole orthogonal-acceleration time-of-flight mass spectrometer , by Hopfgartner, G., Chemushevich, I. V., Covey, T., Plomley, J. B. andBonner, K., Journal of the American Society for Mass Spectrometry, Vo. 10, pp. 1305-1314, Copyright 1999 by the American Society for Mass Spectrometry.

Figure 5.55 MS" spectra from rntz 329, the (M + H)+ ion of an hydroxy metabolite of Praziquantel, and the base peaks in subsequent product-ion spectra. Reprinted from J. Chromatogr., B, 708, Lerch, C. and Blaschke, G., Investigation of the stereoselective metabolism of Praziquantel after incubation with rat liver microsomes by capillary electrophoresis and liquid chromatography-mass spectrometry , 267-275, Copyright (1998), with permission from Elsevier Science.

Residues of PCBs in animal tissues include not only the original congeners themselves, but also hydroxy metabolites that bind to cellular proteins, for example, transthyretin (TTR Klasson-Wehler et al. 1992 Brouwer et al. 1990 Fans et al. 1993). Small residues are also found of methyl-sulfonyl metabolites of certain PCBs (Bakke et al. 1982, 1983). These appear to originate from the formation of glutathione conjugates of primary epoxide metabolites, thus providing further evidence of the existence of epoxide intermediates. Further biotransformation, including methylation, yields methyl-sulfonyl products that are relatively nonpolar and persistent. 

Some hydroxy metabolites of coplanar PCBs, such as 4-OH and 3,3 4,5 -tet-rachlorobiphenyl, act as antagonists of thyroxin (Chapter 6, Section 6.2.4). They have high affinity for the thyroxin-binding site on transthyretin (TTR) in plasma. Toxic effects include vitamin A deficiency. Biomarker assays for this toxic mechanism include percentage of thyroxin-binding sites to which rodenticide is bound, plasma levels of thyroxin, and plasma levels of vitamin A. 

The major metabolite of buprofezin in plants is its p-hydroxy metabolite (p-OH-buprofezin) and that in soil is l-isopropyl-3-phenylurea (BF12). The target analytes are considered to be buprofezin and p-OH-buprofezin in plant materials, buprofezin and BF12 in soils and buprofezin in water samples. 

Lomustine is an orally available nitrosurea alkylating agent. Lomustine is converted rapidly to the cis- and frans-4-hydroxy metabolites the range of half-lives of these two metabolites is 2 to 4 hours.25 Lomustine has shown clinical activity in the treatment of Hodgkin s lymphoma and melanoma. Side effects are similar to those of carmustine. Patients should receive only enough drug for one cycle at a time to prevent confusion and accidental overdose. 

Yue, Q.Y. et al. (1998). Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes. Clin. Pharmacol. Ther., 64, 384-90. 

Zenser, T.V., Lakshmi, V.M. and Davis, B.B. (1999) Human and Escherichia coli /3-glucuronidase hydrolysis of glucuronide conjugates of benzidine and 4-aminobiphenyl, and their hydroxy metabolites. Drug Metabolism and Disposition The Biological Fate of Chemicals, 27, 1064—1067. 

The formation of 0-seryl or 0-prolyl esters (Figure 1) of certain N-hydroxy arylamines has been inferred from the observations that highly reactive intermediates can be generated in vitro by incubation with ATP, serine or proline, and the corresponding aminoacyl tRNA synthetases (11,12,119). For example, activation of N-hydroxy-4-aminoquinoline-l-oxide (119,120), N-hydroxy-4-aminoazobenzene (11) and N-hydroxy-Trp-P-2 (121) to nucleic acid-bound products was demonstrated using seryl-tRNA synthetase from yeast or rat ascites hepatoma cells. More recently, hepatic cytosolic prolyl-, but not seryl-, tRNA synthetase was shown to activate N-hydroxy-Trp-P-2 (12) however, no activation was detectable for the N-hydroxy metabolites of AF, 3,2 -dimethyl-4-aminobiphenyl, or N -acetylbenzidine (122). 

The replacement of chlorine by hydroxyl groups resulting in the formation of hydroxy metabolites, which are excreted or further transformed by conjugation with glucuronic acid... 

The first spectrofluorimetric methods reported for the determination of nalidixic acid and its metabolites in biological fluids did not differentiate between nalidixic acid and hydroxynalidixic acid. The determination of free nalidixic acid and the hydroxy-metabolite in human urine plasma and feces was performed by extraction by toluene from acidified biological fluid and subsequent fluorimetric measurement at 325/375 nm of sample re-extracted into aqueous solution.(8) Conjugated nalidixic and hydroxynalidixic acids were determined by acid hydrolysis and then toluene extraction for fluorimetric measurement of the total drug. The conjugated nalidixic acid was then determined by difference. 

Another drug that is associated with a relatively high incidence of both drug-de-pendent and autoimmune antibodies is diclofenac [38], In some cases the specificity of the diclofenac-induced autoantibodies is very similar to that induced by a-methyldopa [39], Diclofenac is a secondary aromatic amine and is oxidized to reactive metabolites by both cytochromes P450 and myeloperoxidase [40], When patient sera were tested, it was addition of the 4-hydroxy metabolite that most commonly led to agglutination of red cells [41] this metabolite has the potential to be air oxidized to a reactive iminoquinone. 

B) to 90% B in 3.80 min was used, then returned to 20% B at 3.81 min with equilibration until 4.2 min. In the Acquity experiment, the gradient was from 0.25 min (20% B) to 90% B in 1.65 min, maintained at 90% B through 1.90 min, then returned to 20% at 1.91 min with equilibration until 2.10 min. When an injection volume of 30 fiL (from a reconstituted solution volume of 150, uL) was used, the Shimadzu experiment yielded a typical response for 0.955 pg of deslorata-dine and 1.05 pg of its 3-hydroxy analog. In the Acquity experiment, 15 fxL of injection volume was necessary to achieve significantly better signal-to-noise ratio compared to the Shimadzu experiment representing an LLOQ of 0.478 pg for desloratadine and 0.525 pg for the 3-hydroxy metabolite. 

FIGURE 1.21 Structures of omeprazole, its 5-hydroxy metabolite, and desoxyomeprazole (internal standard).136 (Reproduced with permission from Elsevier.)... 

A heritable resistance in pine mice to endrin raises the LD50 from 3 mg/kg in sensitive voles to 40 mg/kg in resistant animals (Webb et al. 1973). This trait is correlated with the greater excretion of endrin as the anti-12-hydroxy metabolite in the resistant mice. Associations between lethality and concentration of 12-ketoendrin residues has been made for rats (Hutson et al. 1975), rat fetuses (Kavlock et al. 1981), and hamster fetuses (Chemoff et al. 1979a). Toxicity also occurs when endrin itself appears in the tissues. 

Lau, Y.Y., Okochi, H., Huang, Y. and Benet, L.Z. (2006) Multiple transporters affect the disposition of atorvastatin and its two active hydroxy metabolites application of in vitro and ex situ systems. Journal of Pharmacology and Experimental Therapeutics, 316, 762-771. 

Crebelli R, Conti G, Carere A. 1987. On the mechanism of mitotic segregation induction in Aspergillus nidulans by benzene hydroxy metabolites. Mutagenesis 2 235-238. 

T. V. Zenser, V. M. Lakshmi, B. B. Davis, Human and Escherichia coli /3-Glucuronidase Hydrolysis of Glucuronide Conjugates of Benzidine and 4-Aminobiphenyl, and Their Hydroxy Metabolites , Drug Metab. Dispos. 1999, 27, 1064 - 1077. 

Anodic oxidation of a suitably unsaturated hydroxyamine was designed for the synthesis of the racemate of an 11-hydroxy metabolite of the important iV-methyl-D-aspartate receptor antagonist MK-0801 [69]. Anodic oxidation of... 

Cheung SW, Tang SW, Remington G. 1991. Simultaneous quantitation of loxapine, amoxapine and their 7- and 8-hydroxy metabolites in plasma by high-performance liquid chromatography. J Chromatogr 564(1) 213-221. 

Pirola R, Mundo E, BeUodi L, Bareggi SR. 2002. Simultaneous determination of clomipramine and its desmethyl and hydroxy metabolites in plasma of patients by high-performance liquid chromatography after solid-phase extraction. J Chromatogr B 772(2) 205-210. 

The metabolites of ondansetron have been examined in urine and bile from rat and dog. The major pathways for metabolism of ondansetron are A-demethylation and hydroxylation Scheme 7.7). However, whereas A-de-methylation predominates in dog, this is only a minor metabolic route in rat. Hydroxylation may occur at the 6, 7 or 8 position in the carbazolone ring. Hydroxy metabolites of ondansetron are excreted predominantly as glucuronide or sulphate conjugates. Studies with immobilised glucuronyl-transferase (Heath, S.E., personal communication) have demonstrated that O- and A-glucuronidation of ondansetron metabolites may occur. 

The N-hydroxylation reaction does not occur in guinea pigs, and this species does not develop cancers in response to aromatic amine exposure. Rats and most other species do, because they possess the enzymes necessary to create N-hydroxy metabolites. Humans also carry these enzymes, so we would expect them, unfortunately, to... 

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