Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.31 (beta-glucuronidase)
 7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolism of 14C-loprazolam has been studied in rat, dog and man in vivo. In rat, the major metabolic pathways were hydroxylation on the benzodiazepine ring, and reduction and acetylation of the nitro group. Both metabolites were identified by co-chromatography with standards, and were present in urine and bile conjugated with glucuronic acid. In both dog and human urine and bile significant amounts of the piperazine-N-oxide were found. This N-oxide was identified by co-chromatography with authentic compound and by mass spectroscopy. Both loprazolam and the dog biliary metabolites were hydrolysed spontaneously to polar material. Neither treatment with beta-glucuronidase nor incubation with gut microflora had any further effect. Only polar metabolites were found in dog and human faeces. The principal non-polar material found in rat plasma was the diazepine-hydroxy compound, and little loprazolam was present. Significant levels of loprazolam and lower levels of an unidentified metabolite were found in ether extracts of dog and human plasma. Both the piperazine-N-oxide and loprazolam were found in similar quantities in chloroform extracts of human plasma, and at two hours after dosage, the N-oxide and loprazolam accounted for greater than 90% of the radioactivity present in the plasma.
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PMID:Metabolism of loprazolam in rat, dog and man in vivo. 665 50

1. The single and multiple dose pharmacokinetics of nefazodone (NEF) and its active metabolites hydroxynefazodone (HO-NEF) and m-chlorophenyl-piperazine (mCPP) were evaluated in subjects classified as extensive metabolizers (EM) or poor metabolizers (PM) of dextromethorphan. 2. In a parallel design study, 10 subjects from each phenotype received either 50 mg or 200 mg oral doses of NEF as single doses on Day 1 and multiple (twice daily) doses on Days 12-22. 3. Serial plasma and urine samples were collected at specified time intervals after dosing on Days 1, 16, 18, 20 and 22. Plasma samples were analyzed for NEF, HO-NEF and mCPP. Urine samples were analyzed for mCPP and its metabolite p-hydroxy-mCPP (p-HO-mCPP) before and after hydrolyzing the samples with beta-glucuronidase. 4. For the 200 mg dose group, the single dose plasma results showed no significant differences in pharmacokinetic parameters for NEF and HO-NEF in EM compared with PM subjects. However, for mCPP, Cmax was 89 ng ml-1 in the PM subjects compared with 44 ng ml-1 in the EM subjects, AUC was higher in the PM than EM subjects (1642 ng ml-1 h and 412 ng ml-1 h, respectively), and mCPP elimination half-life increased from 6.1 h in the EM subjects to 16.4 h in the PM subjects. Upon multiple dosing, plasma levels for NEF and all metabolites reached steady state within 3 days of dosing in both groups of subjects. Steady state pharmacokinetic parameters for NEF and HO-NEF in EM and PM subjects were not significantly different. The steady state Cmax and AUC values for mCPP in the PM subjects were 182 ng ml-1 and 1706 ng ml-1 h, respectively, compared with 49.6 ng ml-1 and 182 ng ml-1 h in the EM subjects. 5. The cumulative urinary excretion of mCPP and p-HO-mCPP was different for EM and PM subjects. Excretion of total mCPP and total p-HO-mCPP was approximately four-fold lower and five-fold higher, respectively, in the EM subjects than PM subjects. 6. These results indicate that the conversion of mCPP to p-HO-mCPP is attributable to metabolism by cytochrome P450 2D6. The differences in mCPP pharmacokinetic parameters in PM subjects did not affect the time required for NEF and its metabolites to attain steady state or the number of adverse experiences in either group of subjects. Based on the results of this study, NEF may be dosed to EM and PM patients without regard to their cytochrome P450 2D6 phenotype.
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PMID:Single and multiple dose pharmacokinetics of nefazodone in subjects classified as extensive and poor metabolizers of dextromethorphan. 895 Nov 88

Glucuronides of piperazine hydroxylamines are rarely reported in the literature, and even more rarely are their structures unambiguously identified. One major metabolite was detected by liquid chromatography/mass spectrometry-radioactivity in urine from monkeys treated with the aryl piperazine oral hypoglycemic agent 9-[(1S,2R)-2-fluoro-1-methylpropyl]-2-methoxy-6-(1-piperazinyl) purine hydrochloride (1). The mass spectrum of this metabolite indicated that it was both monooxygenated and glucuronidated on the piperazine ring. Possible structures included the N- or O-glucuronic acid conjugates of a carbinolamine, hydroxylamine, or N-oxide. Treatment with beta-glucuronidase gave a monooxygenated derivative of the parent compound. 1H NMR analysis of either the glucuronic acid conjugate or the monooxygenated product provided insufficient evidence to unambiguously determine their structures. Incubation of 1 with pig liver microsomes resulted in formation of the same monooxygenated derivative derived from beta-glucuronidase treatment of the glucuronide metabolite. This in vitro system was used to generate sufficient material for analysis by 13C NMR, and the metabolite was identified as a hydroxylamine derivative 2. Incubation of the hydroxylamine with monkey liver microsomes and uridine diphospho-5'-glucuronic acid gave the same glucuronic acid conjugate as that observed in monkey urine. 13C NMR analysis of this biosynthetic product led to its unequivocal structure assignment as the O-glucuronic acid conjugate of the hydroxylamine 3.
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PMID:Identification of a hydroxylamine glucuronide metabolite of an oral hypoglycemic agent. 1474 39

A novel series of nitrogen-containing chalcones were synthesized by Mannich reaction and were screened for anti-inflammatory related activities such as inhibition of cyclooxygenase-2 (COX-2), trypsin and beta-glucuronidase. The antioxidant potential was demonstrated using 1,1-diphenyl-2-picryl hydrazine (DPPH) radical scavenging activity. The results of the above studies shows that the compounds synthesized were found to be effective inhibitors of above pro-inflammatory enzymes, and were found to be possess moderate radical scavenging potential. Overall, the results of the studies reveal that the chalcones with N-methyl piperazine methyl and piperidine methyl substitution (4c, 3b, 4d, 6b) seems to be important for inhibition of beta-glucuronidase. Whereas the chalcones with piperidine methyl substitution (8b, 7b, 7c, 6c, 4b, 3c, 3b) were observed as effective inhibitors of COX-2, while the same compounds were found to be less reactive against COX-1 as compared to COX-2.
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PMID:Synthesis and biological evaluation of nitrogen-containing chalcones as possible anti-inflammatory and antioxidant agents. 2000 7