IV. Effect of Morphine Administration
Abstract
In vivo and in vitro studies of the depressant effect of administered morphine on drug metabolism were conducted with the use of immature and mature male and female rats. In the in vivo studies, morphine increased the hexobarbital sleeping time and hexobarbital blood levels in mature males, but not in immature males or in mature or immature females. In the in vitro studies, administered morphine decreased the metabolism of ethylmorphine and hexobarbital (both type I compounds), cytochrome P-450 levels, and magnitudes of the ethylmorphine and hexobarbital-binding spectra in adult males, but not in immature animals of either sex or in adult females. Aniline metabolism and binding were not affected appreciably in immature or mature rats of either sex. None of these parameters of drug metabolism was affected by morphine administration in adult mice of either sex. Administration of testosterone to developing female rats elevated rates of ethylmorphine and hexobarbital metabolism to levels observed with liver preparations from mature male rats. Morphine administration reversed these elevated rates. Administration of 17β-estradiol to developing male rats prevented the rise in ethylmorphine and hexobarbital metabolism which occurs normally as male rats mature; aniline metabolism remained unaffected. Administration of morphine to estrogen-treated rats had no effect on rates of oxidation of these drugs. Morphine administration to mature male rats raised the ratio of the 455:430 nm peaks of the spectrum of the ethyl isocyanide-cytochrome P-450 complex to approximately that observed with immature males and immature and mature females, which suggests that morphine causes a qualitative change in cytochrome P-450 in adult males. Morphine prevented normal growth of the ventral prostate, an organ known to require androgens for its development. These studies support the concept that administered morphine depresses the metabolism of type I drugs in mature male rats by impairing an androgen-induced stimulation of the hepatic mono-oxidase system.
Footnotes
- Received June 25, 1973.
- Copyright © 1974 by The American Society for Pharmacology and Experimental Therapeutics
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