A MODEL OF HARMINE METABOLISM IN THE RAT

¹ Department of Pharmacology, University of Rochester, Rochester, New York

Previous work from this laboratory has shown that the urinary metabolites of harmine (I) in the rat are harmol (II), harmol glucuronide (III) and harmol sulfate (IV); the rate-limiting step in harmine metabolism is first order with respect to the amount of harmine remaining in the body and occurs before the conjugation reactions. In the present study, biliary and urinary levels of the metabolites were determined after an i.v. dose of 5 mg/kg of I to rats; tissue levels of I were determined over a four-hour period. Metabolites were separated by paper chromatography conjugates were hydrolyzed with -glucuronidase-aryl sulfatase and the concentrations of I and II were determined by quantitative fluorometry. More than 99% of the dose was recovered; 73% was in the bile and 26% was in the urine. Nearly 70% was excreted in the first four hours. Seventy-seven percent was excreted as IV, 21% as III and 1% as I and II. Excretion of IV leveled off after eight hours, whereas excretion of III accelerated, probably due to sulfate depletion. The excretion curve indicated that two compartments contributed to the rate-limiting step. The levels in I in muscle corresponded to one of these compartments, and the levels in the other tissues corresponded to the second compartment. With the experimental data, a model of harmine metabolism was constructed which gave theoretical excretion curves which agreed with the experimental values to within 5%.

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