A-hydroxylated metabolite

Little is known on the metabolic fate of l-methylpyrrolidin-2-one (5.60), an industrial solvent also useful as a solubilizing agent and a penetration enhancer in topical formulations. A preliminary investigation of the disposition and metabolism of labeled l-methylpyrrolidin-2-one in the rat showed that the compound is excreted mainly in urine [171]. Three urinary metabolites were detected, the major of which (ca. 15% of the dose) was 4-(methylami-no)but-2-enoic acid (5.61). This unsaturated product may likely have been formed by H20 elimination from a hydroxylated metabolite. 

Disposition in the Body. Rapidly and completely absorbed after oral administration. About 90% of a dose is excreted in the urine in 48 hours with about 5 to 20% as unchanged drug and about 60 to 80% as a glucuronide conjugate about 5% of the dose is excreted as a hydroxylated metabolite 4-chlorobenzoic acid has been reported to be a minor metabolite. Less than 2% of a dose is eliminated in the faeces. 

Acetonitrile can be acutely lethal when absorbed in high doses. Acetonitrile is metabolized to a hydroxyl metabolite by cytochrome P450 in the liver. Subsequent metabolism through catalase enzymes produces hydrogen cyanide. Once metabolized, the mechanism of action is the same as expected for... 

The possibility of nonenzymatic esterification of free fatty acid by the hydroxylated metabolite was ruled out by two experiments (a) hydroxylated metabolites were Incubated with washed microsomes with no added cofactors, and (b) hydroxylated metabolites were Incubated with different concentrations of fatty acid in buffer without microsomes. In both cases, no detectable fatty acid conjugated metabolites were found by TLC analyses ( 6). 

Furthermore, as shown in Figure 1.10, the 100-nL/min data ideniilied a hydroxylated metabolite with an elution profile close to the parent drug molecule. This hydroxylated metabolite had not been previously observed at 200 uL/niin. The authors propose that the increase in S/N, and decrease in ion suppression, is due to the smaller droplets and higher surface area generated with nanospray. Further support of reduced ion suppression with nanospray has been observed by Schmidt and co-workers [24], provided, however, that... 

In pregnant mice injected intravenously with -labeled 3,3 4-,4 tetraCB (PCB 77), most of the radioactivity was localized in the fetus and consisted mainly of a hydroxylated metabolite (Klasson-Wehler et al. 1989b). However, after a dose of 3,3 fl,4 5-pentaCB (PCB 126), no radioactivity was found in the fetus, except for traces in the liver. This differential distribution is probably due to differences in maternal metabolism for the tetra- and pentachlorobiphenyls (see Section 3.4.3, Metabolism). 

P, but a hydroxylated metabolite, 2,2, 6,6 -tetrachloro-4 -hydroxy-biphenyl, competitively bound to estrogen receptor a and produced proliferative responses in the breast cancer assay at concentrations about 10-fold lower than effective concentrations of the parent molecule (Arcaro et al. 1999). 

A hydroxylated metabolite is inactive, but may be converted back to haloperidol. 

This class of agents is characterized by the l-aryl-3,5-pyrazolidinedione structure. The presence of a proton, which is situated between the two electron-withdrawing carbonyl groups, renders these compounds acidic. The p Ta for phenylbutazone is 4.5. Oxyphenbutazone is a hydroxylated metabolite of phenylbutazone (Figure 13.12). 

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