Effects of metyrapone on the pharmacological activity, plasma levels and urinary excretion of the dopamine receptor agonist DK-118.
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.
D000818:Animals; D001711:Biotransformation; D002415:Cats; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008797:Metyrapone / Q000494:pharmacology*; D009281:Naphthalenes / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000378:metabolism*
D009281:Naphthalenes; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; C031457:DK 118; D008797:Metyrapone