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.
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 17beta-hydroxysteroid dehydrogenase (17beta-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 100 microM or less. Ketoconazole exhibited the lowest inhibitory concentration, and IC(50) and K(i) values of 0.007 and 0.01 microM, 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), verapamil 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 microM) and at the non-clinical overdose concentration (100 microM). Although none of the drugs investigated exhibited inhibitory effects at a concentration of 1 microM, spironolactone and ketoconazole at 100 microM 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 2.4 microM and the latter, 41 microM, 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-hydroxylation 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.
Hokkaido College of Pharmacy, Otaru, Hokkaido, Japan.
Takashi
T
Satoh
Haruka
H
Munakata
Ken-ichi
K
Fujita
Shinji
S
Itoh
Shungo
S
Itoh
Tetsuya
T
Kamataki
Itsuo
I
Yoshizawa
D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D004958:Estradiol / Q000096:biosynthesis* / Q000737:chemistry; D004965:Estrogen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006177:Gynecomastia / Q000139:chemically induced*; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry
D004965:Estrogen Antagonists; D004364:Pharmaceutical Preparations; D011994:Recombinant Proteins; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System