METABOLISM OF ISBUFYLLINE IN HUMANS - ISOLATION, IDENTIFICATION, AND SYNTHESIS OF PLASMA AND URINE METABOLITES

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-h ydroxy-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 (1), 1,3-dimethyl-7-(2-carboxy -propyl) xanthine (IV), and 1,3-dimethyl-7-(2-hydroxymethyl-propyl) xa nthine glucuronic acid (V)-Gluc. They were isolated by HPLC, identifie d by GC/MS, HPLC/MS, or HPLC/MS/MS, and finally synthesized. Recovery of these metabolites, along with the absence of unmetabolized isbufyll ine in the urine, indicated biotransformation and renal excretion as t he 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).