Mice were evaluated for their ability to form phenobarbital N-glucuronides. Following oral administration of [14C]phenobarbital to mice, a radiolabeled phenobarbital metabolite cochromatographed with synthetic standards of phenobarbital N-glucuronides. The phenobarbital N-glucuronides were partially purified from the mouse urine as phenobarbital N-methylglucuronates. The phenobarbital N-methylglucuronates isolated from mouse urine had similar chromatographic and spectroscopic properties as synthetic standards. The diastereomers of phenobarbital N-glucuronides and phenobarbital N-glucosides accounted for 7.8 +/- 2.3% and 1.6 +/- 0.6%, respectively, of the radioactivity excreted in mouse urine in the first 48 hr after dosing. This study indicates that the mouse may be a suitable species to study both N-glucosidation and N-glucuronidation simultaneously as metabolic pathways for barbiturates.
"Regarding the metabolism of barbiturate derivatives, the N-glucoside forms of phenobarbital  and amobarbital  are known as the main metabolites in humans, but no Nglucuronide forms of these compounds have been confirmed . Neighbors et al.  reported the presence of Nglucuronide and N-glucoside in urine of mice treated with phenobarbital, and Mohri et al.  reported the "
[Show abstract][Hide abstract] ABSTRACT: Bucolome N-glucuronide (BCP-NG, main metabolite of bucolome (BCP) is the first N-glucuronide of barbituric acid derivatives isolated from rat bile. The objective of this study was to identify the main tissue producing BCP-NG and the molecular species of BCP-NG-producing UGT. Four target tissues were investigated: the liver, small and large intes-tines, and kidney. To identify the UGT molecular species responsible for BCP-NG formation, yeast microsomes ex-pressing each rat UGT isoform were prepared. BCP-NG formation was detected in all microsomal fractions of the 4 tissues. The liver microsomal BCP-NG-producing activity was the highest, followed by that in the small intestinal mi-crosomes, showing about 41% of the liver microsomal activity level. BCP-NG-producing activity (min-1) was deter-mined in yeast microsomal fractions expressing rat UGT isoforms, and the activity was detected in UGT1A1 (0.059), UGT1A2 (0.318), UGT1A3 (0.001), UGT1A7 (0.003), UGT2B1 (0.004), UGT2B3 (0.091), and UGT2B6 (0.031), show-ing particularly high levels for UGT1A1 and UGT1A2 among the UGT1A isoforms. It was clarified that UGT1A1, widely distributed in rat tissues, is the molecular species responsible for BCP-NG formation.
[Show abstract][Hide abstract] ABSTRACT: A study was undertaken to determine if humans excrete both amobarbital N-glucuronides and N-glucosides in urine after an oral dose of amobarbital. Amobarbital N-glucuronides were synthesized and characterized. A reverse phase LC method using post-column pH adjustment and UV detection at 240 nm was developed and used for the quantification of the amobarbital N-glucosides and N-glucuronides in human urine. Amobarbital was administered orally to seven male subjects and the total urine was collected for a period of 48-53 h after dosing. After filtration, the urine was injected directly onto the HPLC column to analyze for the presence of metabolites. The previously identified (5S)-amobarbital N-glucoside was detected in all seven subjects. The (5R)-amobarbital N-glucoside was detected at lower concentrations in only four of the subjects. At the levels at which amobarbital N-glucosides were detected, there was no evidence for the formation and excretion of the amobarbital N-glucuronides. Amobarbital N-glucuronidation is not a quantitatively significant pathway for the biodisposition of amobarbital in humans.
Journal of Pharmaceutical and Biomedical Analysis 06/1997; 15(8):1187-95. DOI:10.1016/S0731-7085(96)01936-X · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glucosylation of xenobiotics in mammals has been observed for a limited number of drugs. Generally, these glucoside conjugates are detected as urinary excretion products with limited information on their formation. An in vitro assay is described for measuring the formation of the phenobarbital N-glucoside diasteriomers ((5R)-PBG, (5S)-PBG) using human liver microsomes. Human livers (n = 18) were screened for their ability to N-glucosylate PB. Cell viability, period of liver storage, prior drug exposure, serum bilirubin levels, age, sex and ethnicity did not appear to influence the specific activities associated with the formation of the PB N-glucosides. The average rate of formation for both PB N-glucoside was 1.42 +/- 1.04 (range 0.11-4.64) picomole/min/mg-protein with an (5S)-PBG/(5R)-PBG ratio of 6.75 +/- 1.34. The apparent kinetic constants, Km and Vmax, for PB N-glucosylation for eight of the livers ranged from 0.61-20.8 mM and 2.41-6.29 picomole/min/mg-protein, respectively. The apparent Vmax/Km ratio for PB exhibited a greater than 20 fold variation in the ability of the microsomes to form the PB N-glucosides. It would appear that the formation of these barbiturate N-glucoside conjugates in vitro are consistent with the amount of barbiturate N-glucosides formed and excreted in the urine in prior drug disposition studies.
European Journal of Drug Metabolism and Pharmacokinetics 03/2004; 29(1):51-9. DOI:10.1007/BF03190574 · 1.56 Impact Factor
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