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 (EE2) 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 EE2 (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 EE2 (P < 0.05). A similar reduction of cytochrome P450 metabolism by EE2 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 EE2 (P < 0.01). Similar stimulation of glucuronic acid conjugation by EE2 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 EE2 (P < 0.01). This observation appears to be a novel finding with EE2 and cytochrome P450 metabolism. 6. The treatment with OC produced changes in propranolol's metabolic clearances which were qualitatively similar to those generated by EE2.

Treatment of mild hypertension with low once-daily doses of a sustained-release capsule formulation of verapamil.

The efficacy and safety of a low dose (120 mg) of a sustained-release capsule formulation of verapamil administered once daily in the treatment of 42 patients with mild hypertension were assessed in this clinical trial. After a 4-week placebo washout period (baseline), patients with diastolic clinic blood pressures of 91 to 100 mm Hg inclusive were treated for 4 weeks with once-daily verapamil sustained-release 120 mg capsules. Clinic blood pressure was measured and 24-hour ambulatory blood pressure monitoring was performed at the end of both the baseline and the 4-week treatment periods. Twenty-four hour, day, and night systolic and diastolic ambulatory blood pressure were significantly (P < 0.01) reduced in the entire study population (24-hour, -5/-4 mm Hg; day, -6/-4 mm Hg; night, -4/-3 mm Hg). On the basis of mean daytime (6 AM to 6 PM) ambulatory diastolic blood pressure, patients were stratified into subgroups of patients with confirmed (> 85 mm Hg) and unconfirmed mild hypertension (< or = 85 mm Hg). The magnitude of the mean change in systolic and diastolic blood pressure was greater in the group of patients with confirmed mild hypertension than the group with unconfirmed hypertension. The incidence of adverse experiences was low in frequency and events were of mild severity; quality of life scores improved (P = 0.02). Low daily doses (120 mg) of verapamil sustained-release capsules provide a well-tolerated and sustained antihypertensive effect over 24 hours in patients with mild hypertension.

The influence of gender and sex steroid hormones on the plasma binding of propranolol enantiomers.

1. Plasma binding of tritium-labelled racemic propranolol (P) was measured by equilibrium dialysis. The unbound enantiomers were separated by h.p.l.c. after chiral derivatization. The binding of (-)-P was higher than that of (+)-P. 2. Contrary to previous suggestions, a sex difference in the plasma binding of the P enantiomers (9 young women, 12 young men) was not observed. The unbound percentage of (-)-P was 9.2 +/- 1.8 (mean +/- s.d.) in women vs 9.1 +/- 1.7 in men; for (+)-P it was 10.8 +/- 1.8 vs 10.8 +/- 2.1. 3. In the nine women, the binding did not change with fluctuating plasma oestradiol concentrations during the menstrual cycle. Testosterone cypionate doubled the circulating concentrations of testosterone in eight men but had no effect on P binding. 4. Ethinyl oestradiol (50 micrograms day-1) alone or together with norethindrone (OCD) in eight of the women produced an increase in the unbound percentage of both (-)-P (11.4 +/- 2.6 vs 9.5 +/- 1.6 for control; P < 0.001) and (+)-P (13.2 +/- 2.5 vs 11.2 +/- 1.5 for control; P < 0.001). This was due to a decrease in the plasma concentrations of alpha 1-acid glycoprotein from 0.54 +/- 0.11 mg ml-1 in control to 0.37 +/- 0.08 mg ml-1 (P < 0.001) during ethinyl oestradiol treatment. 5. Enantioselectivity in the unbound fraction of P increased with increasing total binding from a (-)/(+)-ratio of 0.93 at 84% binding to a (-)/(+)-ratio of 0.78 at 94% binding (P < 0.001).