Stereoselectivity in the Metabolism of the β-Adrenergic Blocking Agent, (±)-1-tert-Butylamino-3-(2,3-dimethylphenoxy)-2-propanol Hydrochloride (Xibenolol Hydrochloride, D-32), in Man

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After oral administration of deuterium-labeled pseudoracemic D-32 to human subjects, the enantiomeric metabolites in plasma and urine were analyzed by gas chromatography-mass spectrometry. D-32 was biotransformed to 3 major metabolites, 4-hydroxy D-32,3-hydroxymethyl D-32 and 3-carboxy D-32. Twenty-five percent of the racemic dose was excreted into the urine as 4-hydroxy D-32,and 80% of 4-hydroxy D-32 in the urine was derived from (-)-D-32. Sixty percent of 3-carboxy D-32 in the urine was derived from (+)-D-32. About 1% of the racemic dose was excreted into the urine as unchanged material, but of this, in which (+)-D-32 amounted to 3-5 times more than (-)-D-32. The area under the plasma concentration-time curve of (-)-4-hydroxy D-32 was 2.6 times larger than that of (+)-4-hydroxy D-32. The half-lives of (-)-4-hydroxy D-32,(+)-4-hydroxy D-32 and both enantiomers of D-32 were 3.8,2.4 and 3h, respectively. Thus, a marked difference in the metabolism between (-)-D-32 and (+)-D-32 was found. As 4-hydroxy D-32 and 3-hydroxymethyl D-32 are the active metabolites, the pharmacological effectiveness of D-32 after oral administration is represented by the total amount of (-)-4-hydroxy D-32 and (-)-3-hydroxymethyl D-32.
公益社団法人日本薬学会の論文
1985-02-25