17/3-Estradiol metabolism

Schubert W, Cullberg G, Edgar B, Hedner T. Inhibition of 17 beta-estradiol metabolism by grapefruit juice in ovariectomized women. Maturitas 1994 20(2-3) 155-163. 

Michnovicz JJ, Bradlow HL. Induction of estradiol metabolism by dietary indole-3-carbinol in humans. J Natl Cancer Inst 1990 82 947-949. 

Figure 53-1 Main pathways of estradiol metabolism in humans.The circled area represents the site of chemical change.

H9. Heilman, L., Zumoff, B., Fishman, J., and Gallagher, T. F., Estradiol metabolism in total extrahepatic biliary obstruction. /. Clin. Endocrinol. 30, 161-165 (1970). 

Describe the adverse effects of the metabolic products of estradiol metabolism. 

Bradlow HE, Michnovicz J, Telang NT, Oxborne MP, Effects of dietary indole-3carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis 1991 12 1571-1574. 

Niwa T, 8waneck G, Bradlow HL (1994) Alteration in estradiol metabolism in MCF-7 cells induced by treatment with mdole-3-carbinolo and related compounds. 8teroids 59 523-530... 

Both tacrolimus and estradiol are metabolized by CYP3A4 and tacrolimus is a potent inhibitor of 2-estradiol metabolism. Conversely, estradiol inhibits hepatic and intestinal CYP3A4 and reduces tacrolimus metabolism. Transdermal administration avoids hepatic first-pass metabolism, which explains why even small doses have a systemic effect. Co-administration of tacrolimus is possible, but close monitoring of tacrolimus trough concentrations and renal function is necessary. 

Although both estrone and estradiol are available for replacement therapy, they suffer the disadvantage of poor activity on oral administration and short duration of action even when administered parenterally, because of ready metabolic disposition. In order to overcome these deficiencies, there was developed a series of esters of estradiol with long-chain fatty acids. These esters are oil-soluble and correspondingly water-insoluble compounds. 

A major obstacle to the use of naturally occurring estrogens for the purpose of contraception was extensive first-pass hepatic metabolism and hence inactivation of the compounds when given orally. The addition of an ethinyl group at the 17 position made estradiol orally active. Ethinyl estradiol is a potent oral estrogen and... 

Maggs, J.L., Grabowski, P.S., and Park, B.K. (1983). Drug protein conjugates. 2. An investigation of the irreversible binding and metabolism of 17-alpha-ethinyl estradiol in vivo. Biochemical Pharmacology 32, 301-308. 

The most significant metabolic product of testosterone is DHT, since in many tissues, including prostate, external genitalia, and some areas of the skin, this is the active form of the hormone. The plasma content of DHT in the adult male is about one-tenth that of testosterone, and approximately 400 ig of DHT is produced daily as compared with about 5 mg of testosterone. About 50-100 ig of DHT are secreted by the testes. The rest is produced peripherally from testosterone in a reaction catalyzed by the NADPH-depen-dent 5oi-reductase (Figure 42-6). Testosterone can thus be considered a prohormone, since it is converted into a much more potent compound (dihydrotestosterone) and since most of this conversion occurs outside the testes. Some estradiol is formed from the peripheral aromatization of testosterone, particularly in males. 

Ethinyl estradiol is metabolized in the liver via the cytochrome P-450 system. It is metabolized primarily via CYP450 3A4. When reviewing drug interactions of oral contraceptives, it is important to keep in mind that antibiotic administration during contraceptive use may decrease the efficacy of many combined contraceptives. Refer to Table 45-4 for a list of common drug interactions seen with oral contraceptives.1,31... 

One of the routes for metabolism of the natural estrogens involves oxidation at the 16-position. The resulting compounds (estriols) show paradoxical endocrine activities in animal models. Thus, although these metabolites show estrogenic activity in their own right, they can to some extent block the action of concurrently administered estradiol. The unnatural estriol analogue epimestrol (8) shows this kind of activity. 

To reduce conjugative first-pass metabolism and increase the oral bioavailability of P-estradiol, estradiol-3-salicylate, and P-estradiol-3-anthranilate, ester prodrugs were synthesized and their oral bioavailabilities in dogs were evaluated... 

With these promoieties, the 3-phenolic hydroxy group of p-estradiol (the normally metabolized functional group) was blocked so that first-pass conjugative metabolism could be reduced. The relative bioavailability of estradiol was significantly improved when administered in these prodrug forms. A 17-fold increase was observed with the estradiol-3-salicylate. The P-estradiol-3-anthrani-late increased the systemic availability five-fold. 

C Longcope, BG Gorbach, M Woods, I Dwyer, I Warren. The metabolism of estradiol Oral compared to intravenous administration. I Steroid Biochem 23 1065-1070, 1985. 

Estradiol is the predominant and most active form of endogenous estrogens. Given orally, it is metabolized by intestinal mucosa and liver (10% reaches the circulation as free estradiol), and resultant estrone concentrations are three to six times those of estradiol. 

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