Development of Tachyphylaxis to the Antilipolytic, Hypoglycemic Agent, 5-Methylpyrazole-3-carboxylic Acid, U-19425.

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Abstract
Development of tachyphylaxis to U-19425 is described. After 4 days of treatment, rats no longer respond to the pyrazole, U-19425, with a decrease in blood sugar after a challenge dose. The plasma FFA [free fatty acid] response to the drug during the first 30 min. is similar but pretreated rats escape faster from the antilipolytic effects of U-19425 than nonpretreated controls. Lipolytic enzyme systems of pretreated rats may escape faster from the inhibitory effect of U-19425. Tachyphylaxis to the drug may be due to a physiological compensatory mechanism. This mechanism is mediated by the adrenal and/or pituitary since adrenalectomized or hypophysecto-mized rats do not develop tachyphylaxis but hydrocortisone-injected adrenalectomized rats do develop tachyphylaxis to U-19425.