Biological Fate of l-1- (3, 4, 5-Trimethoxybenzyl) -6, 7-dibutyryl-1, 2, 3, 4-tetrahydroisoquinoline Tartrate (BAQ-509) in Rats

Abstract

Absorption, distribution, excretion and metabolism of ³H-l-1- (3, 4, 5-trimethoxybenzyl) -6, 7-dibutyryl-1, 2, 3, 4-tetrahydroisoquinoline (³H-BAQ-509) and ³H-l-1- (3, 4, 5-trimethoxybenzyl) -6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline (³H-AQL-208) in the rat were investigated. When these compounds were orally administered in a dose of 12.5μmoles/kg, BAQ-509 was absorbed more easily than AQL-208. The absorption half-life of BAQ-509 was 80 minutes and that of AQL-208 was 190 minutes. Radioactivity (³H) in each tissue was the highest at one hour after administration of both drugs. When BAQ-509 was administered orally, almost all of the radioactivity in each tissue were found to be due to AQL-208 and its metabolites. The concentration of AQL-208 in the blood, liver, kidney at 20 minutes was 2-11 times higher after administration of BAQ-509 than after administration of AQL-208. Sixty seven per cent of the administered radioactivity of ³H-BAQ-509 was excreted in 48 hour-urine and 29% in 48 hour-feces. It was found that BAQ-509 was hydrolyzed, then was metabolized by either O-methylation or conjugation with glucuronic acid like AQL-208 was metabolized. Of the radioactivity excreted in the 4 hour-urine of rats given ³H-BAQ-509, the largest part (69.3%) was the glucuronide of AQL-208 and 29.3% was the glucuronide of O-methylated AQL-208.
In vitro study of esterase activity showed that the maximum velocity (v max) of esterase in the blood, small intestine and liver homogenates were 1 μmole per minute/ml, 80 μmole per minute/g and 110 μmole per minute/g respectively.