Population study of poor debrisoquine-type metabolizers of propranolol among Japanese

Five healthy male volunteers ingested 40 mg of propranolol in the morning and the blood plasma was analyzed at various intervals by gas chromatography and mass spectrometry. In addition to propranolol, its metabolites 4-OH propranolol, 4-OH propranolol glucuronide and propranolol glucuronide, were found in the plasma. The plasma concentrations of these substances reached maximum levels 2-3 hours after propranolol ingestion. The ratio of propranolol over 4-OH propranolol, (U), and also the ratio of propranolol plus propranolol glucuronide over 4-OH propranolol plus 4-OH propranolol glucuronide (U + G), were calculated. The area under the concentration-time curves (AUC) of these compounds were calculated over 8 hours and the AUC0-8 hr ratios were computed for both (U) and (U + G). The AUC0-8 hr ratio was, in both (U) and (U + G) ratios, linearly correlated with the ratio obtained 2 hours after the propranolol ingestion. Accordingly, the 2-hour values of the (U) or (U + G) ratios were thought to represent the metabolic ratio of the propranolol hydroxylation, and the distribution of these ratios was examined in 162 healthy young male volunteers. Based on the null hypothesis theory, 4 out of the 162 volunteers (2.5%) were judged as poor metabolizers of the debrisoquine-type, ie, hydroxylation of propranolol. The pulse rate, systolic blood pressure and intraocular pressure decreased after propranolol ingestion, the maximum effects being at 2-3 hours after the ingestion. No significant effect was found on the diastolic blood pressure. In the subjects with poor propranolol metabolism, the pharmacological effects of propranolol did not differ significantly from those in other subjects.