Theophylline metabolism by the rat liver microsomal system.

The metabolism of 8-14C-theophylline (14C-Theo) was investigated in vivo and in vitro in the rat. In vivo, 14C-Theo at an initial blood concentration of 10muM was metabolized to at least two different metabolites, 1,3-dimethyl uric acid and 1-methyl uric acid. The biological half-life of the 8-14C-Theo (6 +/- 1.5 hours) was determined from the urinary excretion of radioactivity. Ten days of oral pretreatment of rats with theophylline resulted in a faster rate of metabolism of both 14C-Theo and zoxazolamine. In vitro metabolism of 14C-Theo was investigated in order to identify the enzyme(s) responsible for theophylline metabolism. A tissue survey utilizing tissue slices demonstrated that the metabolism is localized only in the liver since slices of heart, lung, intestine, brain, adrenals, kidney or spleen did not metabolize 14C-Theo. 14C-Theo metabolism in the liver was localized in the subcellular fraction of microsomes and not in the mitochondria or cytosol. 14C-Theo metabolism by liver slices or liver microsomes was inhibited by typical liver microsomal inhibitors such as 2-diethylaminoethyl-2,2-diphenylvalerate (SKF 525-A) and 3-methyl-4-methylaminoazobenzene. 14C-Theo metabolism in liver slices was increased by the liver microsomal-inducing agents, phenobarbital and 3-methylcholanthrene. 3-Methylcholanthrene also increased 14C-Theo metabolism by the liver microsomal fraction. One of the metabolites, 1-methylxanthine, generated by the microsomal system, is a substrate for xanthine oxidase, and its conversion to 1-methyl uric acid by xanthine oxidase was blocked by allopurinol. 14C-Theo per se was shown not to be a substrate for liver xanthine oxidase or aldehyde oxidase. These results indicate that Theo per se is metabolized by the liver microsomal system and not by liver xanthine oxidase or aldehyde oxidase.