Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.
The steroidal estrogens are metabolized principally in the liver, although the kidneys, gonads, and muscle tissues may be involved to some extent. The steroids and their metabolites are conjugated at the hydroxyl group of the C 3 position with sulfuric or glucuronic acid; these conjugates may undergo further metabolic change. Conjugation increases water solubility and facilitates excretion in urine. Large amounts of free estrogens are also distributed into the bile, reabsorbed from the GI tract, and recirculated through the liver where further degradation occurs. /Estrogen General Statement/
The metabolic disposition of estrogens includes oxidative metabolism (largely hydroxylation) and conjugative metabolism by glucuronidation, sulfonation and/or O-methylation. Estradiol is converted to estrone by a 17beta-hydroxysteroid dehydrogenase; the estrone produced is further metabolized to 16alpha-hydroxyoestrone and then to estriol. Hydroxylation of estradiol at the 2 position is a major metabolic pathway in the liver. There are large inter-individual differences in estradiol 2-hydroxylation in human liver samples, which may be reflected by differences in estrogenic action. 4-Hydroxylation of estradiol to a catechol is a minor pathway (usually < 15% of 2-hydroxylation) in the liver.
Estrone sulfate is the estrogen found at the highest concentration in plasma and seems to constitute a storage form for circulating estrogens. Estrone sulfate can be hydrolysed to estrone by arylsulfatases, which are widely distributed in human tissues.
Conjugated equine estrogens are hydrolysed to their active form in the gastrointestinal tract and also undergo considerable hepatic metabolism before entering the bloodstream in an active form. Most sulfate esters are hydrolysed to free or unconjugated estrogen by enzymes in the lower gut; the free estrogen is absorbed by intestinal tissue, where it can be reconjugated with sulfate. Therefore, the estrogen sulfate found in the bloodstream is not the same sulfate that was administered. The rate of dissolution is important because it influences where the active ingredients of the product are released in the gastrointestinal tract, a factor which may affect the amounts of the estrogen that are activated and the patterns of active and inactive metabolites. Equilin and equilenin are interconverted to 17beta-dihydroequilin and 17beta-dihydroequilenin and correspond to the interrelation between estrone and estradiol. As in the case of natural estrogen in women, there is an equilibrium between equilin, equilenin and their metabolites and the respective sulfates.
While early formulations of OCCs were associated with frequent serum enzyme elevations, current formulations and hormonal replacement therapy have not been linked to ALT or alkaline phosphatase elevations at rates any higher than occur with placebo. Estrogens and OCCs can cause mild inhibition of bilirubin excretion, leading to jaundice in patients with inherited forms of bilirubin metabolism such as the Dubin Johnson syndrome. More importantly, estrogens and OCCs can induce a clinically apparent cholestatic liver injury which typically arises during the first few cycles of therapy, and rarely after the six months (Case 1). The onset is typically insidious with fatigue and pruritus, followed by nausea, dark urine and jaundice. Serum enzyme elevations are usually mixed or cholestatic, although very early during the injury, ALT levels can be markedly elevated (5- to 20-fold). The characteristic pattern, however, is bland intrahepatic cholestasis and liver biopsy shows little inflammation or hepatocyte necrosis. Resolution may be delayed (Case 2), but estrogens have not been definitely linked to chronic injury, vanishing bile duct syndrome or acute liver failure. Women with OCC induced cholestasis often have a history of idiopathic cholestasis of pregnancy and there is likely a genetic component, most commonly with variants in the bile salt export pump (BSEP, ABC B11). Estrogens and particularly combinations of estrogens and progestins have been linked to episodes of marked serum aminotransferase elevations without symptoms, jaundice or cholestasis. The abnormalities resolve quickly with stopping the hormonal treatment. This syndrome may be more frequent with progestins than with estrogens alone.
Estrogens and OCCs have also been linked to hepatic tumors, both benign and malignant. Numerous reports of hepatic adenomas have been linked to estrogen and OCC use, typically arising after several years of use and presenting either with pain, liver mass or rupture with hemoperitoneum (Case 3). In population based surveys, the risk of developing hepatic adenomas on OCCs is estimated to be 0.5% per year. In some instances, malignant transformation and hepatocellular carcinoma have been found. Benign tumors may regress to some extent with stopping estrogens, but others require intervention. Estrogens may also promote the growth of other benign liver tumors, such as focal nodular hyperplasia, hemangiomas, and hamartomas.
Hepatocellular carcinoma has been linked to use of oral contraceptives in several case reports and case controlled studies. However, in larger studies and population based analyses, oral contraceptives have not been clearly linked to liver cancer. Hepatocellular carcinoma is extremely rare in young women without accompanying liver disease, and even if oral contraceptives increase the risk of this cancer by 2- to 3-fold, it remains extremely rare.
Use of oral contraceptives has also been linked to an increase in venous thrombosis and cases of hepatic venous thrombosis or Budd Chiari syndrome (Case 4). Women who develop this complication are often found to have other risk factors for venous thromboses such as Protein C or Protein S deficiency or Factor V Leiden. Portal vein thrombosis has also been reported with oral contraceptive use.
Chronic use of oral contraceptives is associated with sinusoidal dilatation, a finding on liver biopsy of uncertain significance. Extreme sinusoidal dilatation associated with venous lakes and propensity for hepatic rupture is referred to as peliosis hepatis, which can be associated with symptoms and hepatic rupture. Oral contraceptive use has been associated with rare instances of peliosis hepatis, but the association a striking dilation of sinusoids with venous lakes has been rarely reported with oral contraceptive use. Stopping oral contraceptives has occasionally been associated with regression in the severity of peliosis.
Both oral contraceptives and chronic hormonal replacement therapy are also associated with a slight increased rate of gallbladder disease, typically occurring during the first few years of estrogen use.
Likelihood score: A (well known cause of various forms of clinically apparent liver injury).
Following oral administration, the natural, unconjugated estrogens are inactivated in the GI tract and liver. Conjugated estrogens and some synthetic derivatives of the natural estrogens may be administered orally. Absorption and metabolism following oral administration of these drugs is rapid and daily doses are usually required. /Estrogen General Statement/
Synthetic conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The Synthetic conjugated estrogens tablet releases the synthetic conjugated estrogens slowly over a period of several hours.
Estrogens are readily absorbed through the skin and mucous membranes. Depending on the amount of estrogen applied, systemic as well as local effects may occur following topical application. /Estrogen General Statement/
The pharmacokinetics of PREMARIN 0.45 mg and 1.25 mg tablets were assessed following a single dose with a high-fat breakfast and with fasting administration. The Cmax and AUC of estrogens were altered approximately 3-13%. The changes to Cmax and AUC are not considered clinically meaningful.
Combinations of lipid modulating agents and substituted azetidinones and treatments for vascular conditions
申请人：Graziano P. Michael
公开号：US20050096307A1
公开（公告）日：2005-05-05
The present invention provides compositions, therapeutic combinations and methods including: (a) at least one lipid modulating agent; and (b) at least one substituted azetidinone or substituted β-lactam sterol absorption inhibitor which can be useful for treating vascular conditions, diabetes, obesity and lowering plasma levels of sterols or 5α-stanols.
Combinations of substituted azetidinones and CB1 antagonists
申请人：Veltri P. Enrico
公开号：US20060069080A1
公开（公告）日：2006-03-30
The present invention provides compositions, therapeutic combinations and methods including: (a) at least one selective CB
1
antagonist; and (b) at least one substituted azetidinone or substituted β-lactam sterol absorption inhibitor which can be useful for treating vascular conditions, diabetes, obesity, metabolic syndrome and lowering plasma levels of sterols or 5α-stanols.
[EN] SUBSTITUTED PIPERAZINES AS CB1 ANTAGONISTS<br/>[FR] PIPÉRAZINES SUBSTITUÉES EN TANT QU'ANTAGONISTES DE CB1
申请人：SCHERING CORP
公开号：WO2009005645A1
公开（公告）日：2009-01-08
Compounds of Formula (I) or pharmaceutically acceptable salts, solvates, or esters thereof, are useful in treating diseases or conditions mediated by CB1 receptors, such as metabolic syndrome and obesity, neuroinflammatory disorders, cognitive disorders and psychosis, addiction (e.g., smoking cessation), gastrointestinal disorders, and cardiovascular conditions.
Azetidinone Derivatives and Methods of Use Thereof
申请人：Aslanian G. Robert
公开号：US20080076750A1
公开（公告）日：2008-03-27
The present invention relates to methods for treating or preventing a disorder of lipid metabolism, pain, diabetes, a vascular condition, demyelination or nonalcoholic fatty liver disease, comprising administering a compound having the formula
or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein:
R
1
and R
2
are defined in Tables 1-6 herein, and
R
3
is -phenyl, -4-chlorophenyl, -2-pyridyl, or -3-pyridyl.
本发明涉及治疗或预防脂质代谢紊乱、疼痛、糖尿病、血管疾病、脱髓鞘或非酒精性脂肪肝病的方法，包括给予具有以下结构式的化合物或其药学上可接受的盐、溶剂化合物、酯、前药或立体异构体：
R
1
和 R
2
在本文的表1-6中定义，并且
R
3
为-苯基、-4-氯苯基、-2-吡啶基或-3-吡啶基。
[EN] AMIDE AND SULFONAMIDE LIGANDS FOR THE ESTROGEN RECEPTOR<br/>[FR] LIGANDS D'AMIDES ET DE SULFONAMIDES DU RECEPTEUR OESTROGENIQUE
申请人：PFIZER PROD INC
公开号：WO2004026823A1
公开（公告）日：2004-04-01
The present invention provides estrogen receptor (ER) ligands of structural formula (I) the pharmaceutically acceptable salts, stereoisomers, and prodrugs thereof, and the pharmaceutically acceptable salts of the prodrugs, wherein R1, R2, R3, R4, R5, X, and Q are as defined herein. The invention further provides pharmaceutical compositions comprising the compounds of formula (I), and methods for treating or preventing diseases, disorders, conditions, or symptoms mediated by an ER which comprise administering to a mammalian subject in need of treatment therewith, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, or a pharmaceutically acceptable salt of the prodrug. The invention further provides pharmaceutical compositions comprising combinations of the compounds of formula (I) and one or more of sodium fluoride, estrogen, a bone anabolic agent, a growth hormone or growth hormone secretagogue, a prostaglandin agonist/antagonist, and a parathyroid hormone, and methods of treating or preventing diseases, disorders, conditions, or symptoms mediated by an ER comprising the administration of an effective amount of such combination to a mammalian subject in need of treatment therewith.
