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.
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