Comparative studies on the effect of adrenocorticotrophic hormone (ACTH) and pregnenolone-16α-carbonitrile (PCN) upon drug response and distribution in rats

Abstract

The effects of pretreatment with pregnenolone-16α-carbonitrile (PCN) or crystalline adrenocorticotrophic hormone (ACTH) and depot ACTH were investigated in female rats given picrotoxin, nikethamide, succinylcholine, strychnine, ethylmorphine, dioxathion, acetanilide, aniline, N-methylaniline, pancuronium, allopurinol, methyprylon, barbital, cyclobarbital, hexobarbital, phenobarbital, zoxazolamine, mephenesin, carisoprodol, sodium aurothiomalate or N-carbamoylarsanilic acid. Both ACTH and PCN offered significant protection against most of the drugs, but nikethamide and dioxathion toxicity was diminished solely by PCN, whereas that of aniline, N-methylaniline, barbital and phenobarbital was decreased by ACTH alone. Time-sequence studies revealed that a single injection of depot ACTH, or PCN gavage, 24 hr prior to zoxazolamine, significantly shortened paralysis. However, a few days of pretreatment with PCN were needed for maximal protection. ACTH, unlike the steroid, reduced zoxazolamine paralysis even in the presence of diethylaminoethyl-2,2-diphenylvalerate (SKF 525-A), a microsomal enzyme inhibitor. Protection by ACTH was not associated with decreased concentrations of zoxazolamine in blood, brain and muscle (syntoxic action). In contrast, PCN lowered the drug level, probably through increased biotransformation and/or excretion (catatoxic action). These findings furnish additional support to the view that catatoxic steroids mostly operate via the induction of drug-metabolizing enzymes in hepatic microsomes, while syntoxic agents augment resistance, probably through altered drug distribution, interactions at receptor sites or decreased receptor sensitivity.