Pharmacokinetics of tetrahydronorharmane (tetrahydro-beta-carboline) in rats.

The distribution, metabolism and elimination into the urine of (14C)-tetrahydronorharmane (THN) as well as of (14C)-6-hydroxy-tetrahydronorharmane (6-OH-THN) are investigated in female and male rats. Following intravenous injection of (14C)-THN radioactivity was detected in all organs examined, namely blood, brain, lung, adrenal gland, small intestine, fat tissue, kidney and liver. In the brain the elimination half life of THN was calculated to be 1.8 h, the elimination half life of the radioactivity in the blood 6.24 h, and the accumulation half life in the urine 9.24 h. The elimination of 6-OH-THN into the urine is faster than that of THN. At least four metabolites of (14C)-THN were found in the urine of female rats. Two different metabolic pathways are discussed, firstly, hydroxylation followed by conjugation with glucuronic and sulfuric acids and secondly, dehydrogenation, followed by oxygenation. In female rats only traces of the conjugated metabolites are hydrolysed by arylsulfatase, whereas in male rats approximately 2/5 are cleaved by this enzyme. Pretreatment of male rats with 3-methylcholanthrene induced conjugation, whereas phenobarbital had no obvious effect on the pattern of metabolites. SKF 525 A and CFT 1201 both prevented almost completely the formation of conjugates from THN.