N-Glucosylation has been thought to be an important pathway for lower life forms but insignificant in mammals. This recent observation that amobarbital and phenobarbital form glucose conjugates and primarily of only one diastereomer suggests that this class of drugs is interfering with a metabolic pathway of unusual specificity. However, the pharmacologic and metabolic importance of this metabolic pathway are unknown. Using the two purified diastereomers of B-D-glucopyrnaosylphenobarbital (pbg and pbg/d), additional studies on the ability of mice to metabolically cleave these conjugates will be studied using normal and germ-free mice, mouse liver homogenates and mouse fecal homogenates. Numerous species (mouse, rat, guinea pig, rabbit, dog, pig and rhesus monkey) will be screened for their ability to form pbg. Currently, only man has been shown to form barbiturate N-glucoside conjugate, therefore, man will be used to determine the structural requirements necessary for a drug to form the N-glucoside metabolites. The expected N-glucoside metabolites will be prepared synthetically and will be used to develop HPLC and GC/MS methods for detecting thse metabolites when excreted in the urine. All drugs observed to form N-glucosides in man will then be studied in the most appropriate animal model found to form pbg. Finally, the methodology used to prepare N-glucosides will be expanded to the synthesis of N-glucuronides.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034507-02
Application #
3285645
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1986-07-16
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Pharmacy
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Nandi, V; Soine, W H (1997) HPLC analysis for amobarbital N-glycosides in urine. J Pharm Biomed Anal 15:1187-95
Neighbors, S M; Soine, W H (1995) Identification of phenobarbital N-glucuronides as urinary metabolites of phenobarbital in mice. Drug Metab Dispos 23:548-52
Soine, W H; Soine, P J; England, T M et al. (1994) Identification of the diastereomers of pentobarbital N-glucosides excreted in human urine. Pharm Res 11:1535-9
Soine, W H; Graham, R M; Soine, P J (1992) Identification of 5-ethyl-5-(2-methylbutyl)barbituric acid as an impurity of manufacture in amobarbital. J Pharm Sci 81:362-4
Soine, W H; Safi, H; Westkaemper, R B (1992) Initial studies on the N-glucosylation of phenobarbital by mouse liver microsomes using a radiochemical high-performance liquid chromatographic (HPLC) method. Pharm Res 9:613-6
Soine, W H; Soine, P J; England, T M et al. (1991) Identification of phenobarbital N-glucosides as urinary metabolites of phenobarbital in mice. J Pharm Sci 80:99-103
Mongrain, S E; Soine, W H (1991) Product enantioselectivity in the N-glucosylation of amobarbital by cats. Drug Metab Dispos 19:1012-3
Soine, W H; Soine, P J; England, T M (1991) Barbital N-glucoside is not detected as a urinary excretion product of barbital in humans. J Pharm Biomed Anal 9:747-52
Soine, W H; Soine, P J; England, T M et al. (1990) LC determination of the diastereomers of 1-(beta-D-glucopyranosyl)phenobarbital in human urine. J Pharm Biomed Anal 8:365-72
Soine, W H; Soine, P J; Wireko, F C et al. (1990) Stereochemical characterization of the diastereomers of the amobarbital N-glucosides excreted in human urine. Pharm Res 7:794-800

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