Ketoconazole is an orally active imidazole antifungal agent that inhibits the activities of CYP3A4 and CYP24A1. Ketoconazole disrupts fungal cell membrane integrity by inhibiting cytochrome P450 14α-demethylase and blocking ergosterol synthesis. Ketoconazole reduces androgen synthesis by inhibiting 17α-hydroxylase and 17,20-lyase. Ketoconazole can be used in research related to fungal infections, prostate cancer, and Cushing syndrome[1-4].
In vitro, treatment of human osteosarcoma MG63 cells with 20-200μM Ketoconazole for 24 hours reduced cell viability and induced apoptosis, elevated intracellular Ca2+ concentration, and induced ERK and JNK phosphorylation[5]. Pretreatment of J774 cells with 10μg/mL Ketoconazole for 30 minutes followed by treatment with 10μg/mL lipopolysaccharide for 24 hours decreased nitrite levels in culture supernatants and reduced i-NOS mRNA expression in cells[6]. Treatment of CEM-C7 cells with 18.8-90μM Ketoconazole for 90 hours inhibited cell growth[7].
In vivo, a single oral administration of 300mg/kg Ketoconazole to male rats decreased serum testosterone and corticosterone levels and reduced epididymal sperm motility[8]. Daily topical application of 2% Ketoconazole solution (0.1mL per application, 5 days per week) to the dorsal skin of depilated C3H/HeN mice for 3 weeks promoted hair regrowth and stimulated telogen-to-anagen transition[9]. Oral administration of 10mg/kg Ketoconazole to Schistosoma mansoni-infected CD1 Swiss albino mice on days 47, 48, and 49 post-infection, followed by a single oral dose of 400mg/kg quinine 2 hours after the last Ketoconazole dose, inhibited hepatic CYP450 and CYT b5 activities, reduced female worms, total worms, hepatic egg burden, and intestinal egg burden, shrank liver granuloma diameter, and increased the percentage of dead eggs[10].
References:
[1] Hume AL, Kerkering TM. Ketoconazole. Drug Intell Clin Pharm. 1983 Mar;17(3):169-74.
[2] Galgiani JN. Ketoconazole in the treatment of coccidioidomycosis. Drugs. 1983 Oct;26(4):355-63.
[3] Scheinfeld N. Ketoconazole: a review of a workhorse antifungal molecule with a focus on new foam and gel formulations. Drugs Today (Barc). 2008 May;44(5):369-80.
[4] Ji Y, Wang Y, Liu Y, et al. The Effect of Ketoconazole and Quinestrol Combination on Reproductive Physiology in Male Mice. Animals. 2024 Nov;14(22):3240.
[5] Lin KL, Huang CC, Cheng JS, et al. Ketoconazole-induced JNK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells. Toxicol In Vitro. 2009 Dec;23(8):1268-1276.
[6] Baroni A, Ruocco V, De Paolis P, et al. Ketoconazole inhibits lipopolysaccharide-induced activation of the nitric oxide synthase gene in the murine macrophage cell line J774. Arch Dermatol Res. 1999;291(1):54-58.
[7] Hackney JF, Schwartz DA, et al. Ketoconazole inhibition and glucocorticoid action in the human lymphoblastic leukemia cell line CEM-C7. J Steroid Biochem. 1988;29(1):15-19.
[8] Heckman WR, Kane BR, Pakyz RE, et al. The effect of ketoconazole on endocrine and reproductive parameters in male mice and rats. J Androl. 1992 May/Jun;13(3):191-198.
[9] Jiang J, Tsuboi R, Kojima Y, et al. Topical application of ketoconazole stimulates hair growth in C3H/HeN mice. J Dermatol. 2005;32(4):243-247.
[10] Seif el-Din SH, Sabra AN, Hammam OA, et al. Effect of Ketoconazole, a Cytochrome P450 Inhibitor, on the Efficacy of Quinine and Halofantrine against Schistosoma mansoni in Mice. Korean J Parasitol. 2013 Apr;51(2):165-175.