S t a t e U n i v e r s i t y , Boise, ID 83725 ** C l i n i c a l Pharmacology and Gerontology U n i t , Veterans A d m i n i s t r a t i o n Medical Center, Boise, I D 83702 and Oivison o f Gerontology & G e r i a t r i c Medicine, Department o f Medicine, U n i v e r s i t y o f Washington, S e a t t l e , WA SUmARY Four i s o t o p i c a l l y l a b e l l e d metabolites o f t h e o p h y l l i n e were synthesized. The syntheses of l-(methyl-dj)uric-2,8-13C2-acid; 1,3-di(methyl-d3)uric-2,8-13C2 acid; 3-(methyl -d3 )xanthIne-2-1% ,7-15N and 1-(methyl -d3 Ixanthine-2-13C are described. M o d i f i c a t i o n s i n pub1 ished procedures f o r the synthesis o f the corresponding unlabel l e d compounds were r e q u i r e d t o achieve the micro scale necessary t o accommodate the small s t a r t i n g q u a n t i t i e s o f expensive s t a b l e i s otope l a b e l l e d precursors. KEY WORDS: theophyll i n e metabolites, 1-methyluric a c i d , 1,3-dimethyluric acid, 1-methyl xanthine, 3-methyl xanthine, s t a b l e isotope 1 abel 1 i ng I NTRODUCTI ON Theophylline i s a drug which i s f r e q u e n t l y used i n the acute and chronic management o f o b s t r u c t i v e airways disease. Recent studies ( 1 -3 ) o f the d i s p o s it i o n o f t h i s important, b u t p o t e n t i a l l y t o x i c , therapeutic agent have u t i l i z e d s t a b l e isotope methodology ( 4 ) i n order t o o b t a i n estimates o f the pharmacokine t i c parameters a t steady s t a t e under c o n d i t i o n s o f chronic dose a d m i n i s t r a t i o n .