Effects of oral contraceptives and tobacco use on the metabolic pathways of theophylline

The effects of chronic oral contraceptive (OC) use and cigarette smoking on the metabolism of theophylline (THEO) were investigated in 22 healthy female volunteers. Blood and urine samples were collected over 23 h following oral aminophylline dosing. Urine was assayed by HPLC for both unchanged theophylline and its primary metabolites (3-methylxanthine (3-MX), 1-methyluric acid (1-MUA) and 1,3-dimethyluric acid (1,3-DMUA)). The metabolite formation clearances for the subject groups appeared linear except for a Michaelis-Menten pattern in the non-OC users who smoked. Smoking increased metabolite formation clearances for 3-MX (by 55%), 1-MUA (by 49%) and 1,3-DMUA (by 26%). Chronic OC exposure resulted in reductions for 3-MX (by 42%), 1-MUA (by 24%) and 1,3-DMUA (by 19%). Renal clearances of unchanged theophylline were urine flow-dependent and affected secondarily by OC and tobacco use. While 3-MX formation is most sensitive to change, the differential effects from enzyme induction by tobacco and inhibition by OC suggests that each pathway has differing sources of enzymatic regulation.