title: The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins.
abstract: Ketoconazole an orally active imidazole drug and bifonazole, clotrimazole, econazole, isoconazole, miconazole and tioconazole are known inhibitors of cytochrome P-450 dependent steroidogenic enzymes. The aim of the present study was to determine whether these imidazole drugs also have an effect on [3H]R1881 binding to the human prostatic androgen receptor, [3H]5 alpha-dihydrotestosterone (5 alpha-DHT) binding to plasma sex hormone binding globulin (SHBG) and [3H]cortisol binding to plasma corticosteroid binding globulin (CBG). In comparison the effect of both steroidal (cyproterone acetate; CPA) and non-steroidal (anandron, flutamide, hydroxyflutamide, ICI 176344) antiandrogens on these steroid binding proteins was also determined. The results of the present study show that the imidazole drugs were without effect on [3H]R1881 binding to the androgen receptor and on [3H]cortisol binding to CBG up to 100 mumol/l. However, they were weak competitors of [3H]5 alpha-DHT binding to SHBG inhibiting 20-53% of binding at 100 mumol/l. In comparison the antiandrogens were strong competitors of [3H]R1881 binding to the androgen receptor, the order of decreasing potency, determined from ID50 (mumol/l) values were CPA (0.073) greater than ICI 176344 (0.4) greater than anandron (0.63) greater than hydroxyflutamide (1) greater than flutamide (greater than 100). The non-steroidal antiandrogens were without effect on [3H]cortisol binding to CBG whereas CPA caused 36% inhibition of binding at 100 mumol/l. Of the antiandrogens studied CPA was the strongest competitor of [3H]5 alpha-DHT binding to SHBG with an ID50 of 23 mumol/l, in contrast the non-steroidal antiandrogens were weak competitors causing less than 40% inhibition at 100 mumol/l. It is concluded that the primary mode of action of the imidazole drugs is through the inhibition of cytochrome P-450 dependent steroidogenic enzymes with little or no effect on steroid binding proteins. In comparison, the antiandrogens were strong competitors of [3H] binding to the androgen receptor but relatively weaker competitors of [3H] steroids binding to plasma binding proteins.
authors: Department of Chemical Pathology, University of Leeds, England, U.K.
authors: M
authors: M
authors: Ayub
authors: M J
authors: MJ
authors: Levell
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D013196:Dihydrotestosterone / Q000097:blood*; D004963:Estrenes / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D015741:Metribolone; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*; D045165:Testosterone Congeners / Q000378:metabolism
chemical_list: D000726:Androgen Antagonists; D001798:Blood Proteins; D004963:Estrenes; D007093:Imidazoles; D011944:Receptors, Androgen; D045165:Testosterone Congeners; D013196:Dihydrotestosterone; D015741:Metribolone; D007654:Ketoconazole; D006854:Hydrocortisone