Effects of metyrapone on the pharmacological activity, plasma levels and urinary excretion of the dopamine receptor agonist DK-118.

Abstract

Possible metabolic activation of the dopamine receptor agonist DK-118 (5-hydroxy-6-methyl-N,N-di-n-propyl-2-aminotetralin) was investigated in cats. Metyrapone, an inhibitor of oxidative drug metabolism, was given to cats before DK-118 and the pharmacologic effects of the dopamine agonist were compared to those observed in nonpretreated animals. A sensitive high-performance liquid chromatography assay using electrochemical detection was developed to monitor urine and plasma concentrations of DK-118 in metyrapone-pretreated and control animals. The DK-118-mediated inhibition of cardioaccelerator nerve stimulation-induced tachycardia was reduced markedly in cats pretreated with metyrapone but the pretreatment had no effect on the hypotension or bradycardia produced by DK-118. In a separate group of cats, the tachycardia inhibitory effect of a nonbioactivated dopamine agonist, dipropyldopamine, was unaffected by metyrapone pretreatment, confirming that the inhibitor of drug metabolism does not interfere with this dopamine receptor-mediated effect. Pretreatment with metyrapone before a 0.14-mumol/kg i.v. dose of DK-118 increased the half-life, reduced total drug clearance and increased urinary excretion of unchanged DK-118. All of the changes are consistent with a metyrapone-related inhibition of DK-118 metabolism. The results of this study show that inhibition of DK-118 metabolism reduces certain of its pharmacologic actions, indicating that one or more of the metabolites of the drug may contribute to its effects.

• Authors: J C Koons, J P Long, D L Koble, J G Cannon, L J Fischer
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 233 Issue 1 Pg. 51-7 (Apr 1985) ISSN: 0022-3565 [Print] United States
• PMID: 3920384 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Naphthalenes
• Receptors, Dopamine
• Tetrahydronaphthalenes
• DK 118
• Metyrapone

Topics

• Animals
• Biotransformation
• Cats
• Female
• Heart Rate (drug effects)
• Kinetics
• Male
• Metabolic Clearance Rate (drug effects)
• Metyrapone (pharmacology)
• Naphthalenes (metabolism)
• Receptors, Dopamine (metabolism)
• Tetrahydronaphthalenes (metabolism)