Stimulatory as well as inhibitory effects of ethinyloestradiol on the metabolic clearances of propranolol in young women

1 The metabolism of a single 80 mg oral dose of propranolol was determined in nine young women before and after administration of ethinyloestradiol alone (EE(2)) or in combination with norethindrone (OC). 2 Whereas the total clearance of propranolol (2713 +/- 404 ml min(-1) (mean +/- s.e.mean)) was not significantly altered by either EE(2) (3365 +/- 347 ml min(-1)) or the combined OC (2905 +/- 345 ml min(-1)), significant changes in all three primary metabolic pathways were observed. 3 The clearance through side-chain oxidation decreased from 345 +/- 55 ml min(-1) to 262 +/- 33 ml min(-1) after EE(2) (P < 0.05). A similar reduction of cytochrome P450 metabolism by EE(2) has been observed for other drugs. 4 The clearance through glucuronidation increased from 364 +/- 61 ml min(-1) to 625 +/- 117 ml min(-1) after EE(2) (P < 0.01). Similar stimulation of glucuronic acid conjugation by EE(2) has also been observed for other drugs. 5 The clearance through ring oxidation increased from 697 +/- 109 ml min(-1) to 1280 +/- 162 ml min(-1) after EE(2) (P < 0.01). This observation appears to be a novel finding with EE(2) and cytochrome P450 metabolism. 6 The treatment with OC produced changes in propranolol's metabolic clearances which were qualitatively similar to those generated by EE(2).