The ability to hydroxylate debrisoquine is known to be polymorphically distributed, with about 8% to 9% of the North American Caucasian population being poor metabolizers. We have shown that the ability to 4-hydroxylate propranolol is also polymorphically determined and that it cosegregates with ability to metabolize debrisoquine, such that poor debrisoquine metabolizers produce much less 4-hydroxypropranolol (4-OH propranolol) than do extensive metabolizers. There was no significant difference, however, between plasma propranolol concentrations after either single or multiple doses in the two groups. Despite the substantial difference in production of the pharmacologically active 4-OH metabolite, no difference was seen in the extent of beta-blockade induced in the extensive and poor metabolizers, which implies that 4-OH propranolol does not contribute substantially to beta-blockade.

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Pretreatment by inhalation with the alpha 1-adrenergic agonist methoxamine and the "loop" diuretic frusemide reduces the bronchial response to certain airway challenges in asthma. To test whether these drugs may act by altering airway epithelial ion and water transport, their effect on nasal potential difference (PD) when applied topically in eight normal volunteers was measured. For comparison, the effect of the Na(+)-channel blocking drug amiloride and the beta 2-adrenergic agonist salbutamol was also tested. Both methoxamine and frusemide significantly reduced PD: at the highest concentration given (10(-3) mol.l-1), there was a mean drop in PD from baseline of 39.5% following methoxamine treatment (p less than 0.05) and a mean drop of 30.2% following frusemide (p less than 0.05). Neither drug was as effective as amiloride, which caused a mean drop in PD of 27.5% from baseline at 10(-6) mol.l-1 and a drop of 71.6% at 10(-3) mol.l-1 (p less than 0.01 for each concentration). Salbutamol had no significant effect on PD (p greater than 0.05). We conclude that methoxamine and frusemide may derive their protective effect on some bronchial challenge, at least in part, from their effect on airway epithelial ion flux.

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