Ketoconazole inhibits the in vitro and in vivo metabolism of all-trans-retinoic acid.

Ketoconazole, an antifungal agent and inhibitor of certain mammalian cytochrome P-450-dependent enzymes, was studied for its effects on the in vitro and in vivo metabolism of all-trans-retinoic acid (RA). In vitro, ketoconazole (Ki = 0.75 microM) inhibited, in an apparently competitive manner, the cytochrome P-450-mediated metabolism to 4-hydroxy- and 4-keto-retinoic acids by hamster liver microsomes. In vivo, ketoconazole suppressed the formation of polar RA metabolites by normal rats dosed intrajugularly with 200 ng of [3H]RA. After p.o. treatment with ketoconazole (2.5-40 mg/kg) given 1 hr before the [3H]RA injection, the radioactivity extracted from the liver consisted of 25 to 50% polar metabolites (control 66 +/- 1%) and 50 to 75% undegraded RA (control 34 +/- 1%) as evidenced by reverse-phase high-performance liquid chromatography. Time course experiments showed that ketoconazole's inhibitory effects lasted for 3 hr. Our data indicate the quantitative importance of the cytochrome P-450 enzymatic pathway in the biotransformation of RA. They also suggest that ketoconazole is capable of prolonging the biological half-life of RA and of improving the tissue levels of this compound.

Effect of levamisole on autologous rosette-forming cells in nude mice.

Levamisole depresses the number of autologous rosette-forming cells (ARFC) in the spleen of nude (congenitally athymic) mice. Intravenous administration of 2.5 mg/kg of levamisole produces maximal depression. This effect appears 15 h after injection and is transient, partially disappearing after 48 hr. Dexamisole is devoid of this depressing activity. Thymopoietin, a thymic hormone, is also shown to lower the level of autologous rosette formation. These results suggest a stereospecific interference of levamisole with the maturation of immature T-cell precursors in a manner resembling the action of thymic hormones.