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Pharmacokinetics of the new antihypertensive agent nipradilol in rats. 1st communication: Metabolism and disposition after single oral administration of [14C]nipradilol.

The metabolism and disposition of a new antihypertensive and antianginal agent, 3,4-dihydro-8-(2-hydroxy-3-isopropylamino)propoxy- 3-nitroxy-2H-1-benzopyran (nipradilol, K-351) were studied using its [14C]-labelled compound in rats. The plasma level of radioactivity reached the maximum 1 h after oral administration, and the majority of radioactivities administered were recovered in urine and via the bile in feces within 48 h. From the foregoing it is obvious that the drug was absorbed from the gastrointestinal tract rapidly and well, and was eliminated from the body completely. The unchanged drug detected in the plasma and urine after oral administration of 30 mg/kg was more than 10 times as much as that after 3 mg/kg. This fact indicates that the first-pass metabolism of the drug has been saturated. Denitronipradilol, 4- and 5-hydroxynipradilol, and 4- and 5-hydroxydenitronipradilol were identified as major metabolites in the plasma and excreta, and the degradation compounds of the aminohydroxypropoxy side chain were also found as minor metabolites. Among these metabolites, 4-hydroxy metabolites were found mainly as unconjugates and 5-hydroxy metabolites as glucuronides, respectively. These findings suggest that the possible metabolic pathways of nipradilol in rats involve reductive denitration of the nitroxy group, hydroxylation at the benzopyran skeleton, oxidative degradation of the beta-blocking side chain and their glucuronidation.