title: Metabolism of isbufylline in humans. Isolation, identification, and synthesis of plasma and urine metabolites.
abstract: Isbufylline metabolism after oral administration to humans was studied. The main metabolites detected by the HPLC method, in plasma, were 1-methyl-7-(2-hydroxy-2-methyl-propyl) xanthine (I), 1,3-dimethyl-7-(2-hydroxy-2-methyl-propyl) xanthine (II), and 1-methyl-7-(2-methyl-propyl) xanthine (III). The main metabolites detected in urine were 1-methyl-7-(2-hydroxy-2-methyl-propyl) xanthine (I), 1,3-dimethyl-7-(2-carboxy-propyl) xanthine (IV), and 1,3-dimethyl-7-(2-hydroxymethyl-propyl) xanthine glucuronic acid (V)-Gluc. They were isolated by HPLC, identified by GC/MS, HPLC/MS, or HPLC/MS/MS, and finally synthesized. Recovery of these metabolites, along with the absence of unmetabolized isbufylline in the urine, indicated biotransformation and renal excretion as the main routes of isbufylline elimination in humans. HPLC quantitation of the characterized urine metabolites revealed that 49% of the drug was eliminated as (I), 9% as (V)-Gluc, and 5% as (IV).
authors.affiliation: Analytical and Chemical Department, Istituto Farmacobiologico Malesci S.p.A., Florence, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Agostini
authors.forename: G
authors.initials: G
authors.lastname: Bonacchi
authors.forename: G
authors.initials: G
authors.lastname: Coppini
authors.forename: E
authors.initials: E
authors.lastname: Toja
authors.forename: A
authors.initials: A
authors.lastname: Triolo
authors.forename: S
authors.initials: S
authors.lastname: Manzini
authors.forename: G
authors.initials: G
authors.lastname: Pieraccini
authors.forename: G
authors.initials: G
authors.lastname: Moneti
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D000284:Administration, Oral; D001711:Biotransformation; D001993:Bronchodilator Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006868:Hydrolysis; D007202:Indicators and Reagents; D008297:Male; D013058:Mass Spectrometry
chemical_list: D001993:Bronchodilator Agents; D007202:Indicators and Reagents; C058878:isbufylline; D015056:1-Methyl-3-isobutylxanthine