Stereoselectivity in the metabolism of the .BETA.-adrenergic blocking agent, (.+-.)-1-tert-butylamino-3-(2,3-dimethylphenoxy)-2-propanol hydrochloride (xibenolol hydrochloride, D-32), in man.

Abstract

After oral administration of deuterium-labeled pseudoracemic D-32 [a cardiovascular drug] 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. Of the racemic dose 25%, 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. Of 3-carboxy D-32 in the urine 6%, was derived from (+)-D-32. About 1% of the racemic dose was excreted into the urine as unchanged material, but of this, (+)-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 3 h, respectively. 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 metabolities, 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.