Studies on the Interactions between Drug and Estrogen. II. On the Inhibitory Effect of 29 Drugs Reported to Induce Gynecomastia on the Oxidation of Estradiol at C-2 or C-17

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A study was investigated on the inhibitory effect of 29 drugs that have been reported to induce gynecomastia on the 2-hydroxylation of estradiol (E2) by recombinant P450 CYP3A4 and on the 17-oxidation of E2 by hepatic microsomal type II 17β-hydroxysteroid dehydrogenase (17β-HSD) of human male. The IC_<50> values were determined for each drug relative to the 2-hydroxylation of E2 (catalytic activity: 1.54 nmol/nmol P450/min), and the inhibition constants (K_I) were determined for 13 drugs of which IC_<50> values were 100μ_M or less. Ketoconazole exhibited the lowest inhibitory concentration, and IC_<50> and K_I values of 0.007 and 0.01 μ_M, respectively, were obtained. The IC_<50> and K_I values for each of the 12 remaining drugs were as follows: cyclosporin A (IC_<50>: 0.064, K_I:0.30), nicardipine hydrochloride (0.55, 0.29), tacrolimus (0.64, 0.88), mandipine hydrochloride (3.9, 2.6), nisoldipine (10, 3.3), vcrapamil hydrochloride (10, 20), domperidone (13, 7.2), haloperidol (14, 55), nitrendipine (14, 2.5), chlormadinone acetate (16, 10), flutamide (30, 39) and omeprazole (49, 47). With the exception of cyclosporin A that exhibited a competitive inhibition, the inhibition mechanisms of these drugs were all non-competitive. Next, the percentage inhibition of the above 29 drugs relative to the 17-oxidation of E2 (catalytic activity: 0.47 nmol/mg protein/min) was investigated at the approximate therapeutic concentration (1 flM) and at the non-clinical overdose concentration (100 μ_M). Although none of the drugs investigated exhibited inhibitory effects at a concentration of 1μ_M, spironolactone and ketoconazole at 100 μ_M demonstrated percentage inhibitions of 96% and 77%, respectively. When the K_I values were determined for these two drugs, the former had a K_I value of 2.4μ_M and the latter, 41 μ_M, and both of their inhibition mechanisms were non-competitive. On the basis of the above results, a total of 14 drugs consisting of the above 13 drugs plus spironolactone were found to inhibit the 2-hy-droxylation or 17-oxidation of E2 in the liver, and this is presumed to act as a trigger that causes as increase in the estradiol pool, followed by induction of gynecomastia.
公益社団法人日本薬学会の論文
2003-05-01

Studies on the Interactions between Drug and Estrogen. II. On the Inhibitory Effect of 29 Drugs Reported to Induce Gynecomastia on the Oxidation of Estradiol at C-2 or C-17

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