A population study of the poor metabolizers of the debrisoquine type in Japan
Hayashi, M.; Takase, M.
Nippon Ganka Gakkai Zasshi 89(8): 983-990
1985
ISSN/ISBN: 0029-0203 PMID: 4072846 Document Number: 252677
Recently ophthalmic administration of timolol came into use for glaucoma in Japan and it has been found that there is a difference between Japan and U.S.A. in the incidence of the systemic adverse effects of timolol. Several causes may be attributed to it, one of which is a pharmacogenetical factor. Metabolism of timolol is under the same genetic control as polymorphic hydroxylation of debrisoquine and its poor metabolizers are known at a risk of concentration-dependent side effects. Ethnic differences have been observed in the incidence of poor metabolizers, however, Japanese incidence has not been reported so far. Therefore, the aim of this work is to study the Japanese metabolic ability. The result using propranolol as the parent drug is as follows. 1. Time course study. The plasma of five healthy volunteers was collected at planned intervals up to eight hours after they ingested 40 mg of propranolol in the morning when fasting and analyzed by gas chromatography and mass spectrometry. The plasma concentration increased in the order of propranolol, 4-OH propranolol, 4-OH propranolol glucuronide, and propranolol glucuronide. They reached their maximum concentration after two or three hours, decreasing linearly on the logarithmic scale. 2. Population study. Metabolic ratios of 162 healthy volunteers were calculated on plasma concentration at two hours after ingestion. Five subjects were poor metabolizers by the metabolic ratio of free propranolol to free 4-OH propranolol with null hypothesis theory (P < 0.01). Four subjects proved to be poor metabolizers by the metabolic ratio corrected by adding each glucuronide to propranolol and 4-OH propranolol. Two subjects were in common to both ratios. 3. Four subjects in 162 volunteers (2.5%) were considered poor metabolizers of the debrisoquine type in Japanese.