Inhibition of human lung cyclic nucleotide phosphodiesterases by proxyphylline, theophylline and their metabolites.

Inhibition of cAMP and cGMP hydrolysis in human lung tissue by proxyphylline and its main metabolite 1-methyl-7-(beta-hydroxypropyl)xanthine was compared with theophylline and its metabolite 3-methylxanthine. The apparent inhibition constant of proxyphylline was 0.06-0.7 mmol/l at low cAMP concentrations and at low and high cGMP concentrations, while it was 1.0 mmol/l at high cAMP concentrations. This is 1.2-1.7 times higher than the corresponding values for theophylline. Both metabolites were slightly weaker inhibitors than their parent drugs, the theophylline metabolite relatively weaker than the proxyphylline metabolite. The differences in the observed inhibition constants agree with previous clinical studies indicating that the potency of theophylline is approximately twice that of proxyphylline.