Raloxifene hydrochloride:Chemical structure and Pharmacokinetics

Introduction

Raloxifene hydrochloride is a selective estrogen-receptor modulator (SERM) that has been approved for use in the prevention and treatment of osteoporosis in postmenopausal women. Because raloxifene hydrochloride has estrogen agonist-like effects on bone and on cholesterol metabolism and antagonist-like effects on the endometrium and breasts, it has the potential to produce some of the beneficial effects of estrogen without the possible adverse effects.[1] Exhibiting tissue-specific effects distinct from estradiol, raloxifene is the first of the benzothiophene group of antiestrogens to be labelled a SERM. Available in many countries worldwide, raloxifene hydrochloride was initially approved by the FDA in December, 1997 under the market name Evista® for the management and prevention of osteoporosis in postmenopausal women and reduction in risk for invasive breast cancer in postmenopausal women with osteoporosis or those who are at high risk for invasive breast cancer. However, it has a negligible effect on altering the development and progression of breast cancer itself. The most common causes of osteoporosis include postmenopausal deficiency of estrogen and age-related deterioration in bone homeostasis. Due to the risk of bone fractures that may lead to morbidities and reduced quality of life, the management of osteoporosis in postmenopausal women with the use of therapeutic agents in addition to concurrent therapies is critical. Due to the decline in estrogen levels in postmenopausal osteoporosis, hormone replacement therapy (HRT), such as estradiol, has been used to ameliorate the condition. However, due to the off-target actions by HRT, newer non-hormonal agents such as raloxifene and tamoxifen have been developed to reduce adverse events through selective pharmacological actions on tissue-specific therapeutic targets.[2]

Chemical structure

Raloxifene hydrochloride is a benzothiophene nonsteroidal derivative that binds to the estrogen receptor. It is classified as a selective estrogen-receptor modulator. The chemical name is [6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl] hydrochloride.[1] Several modifications to the 2-arylbenzothiophene core have shown that the 6-hydroxy and the 4’-hydroxy substituents of raloxifene are important for estrogen receptor binding and for mimicking the corresponding 3- and 17β-hydroxy groups of 17β-estradiol. (Fgiure 1) An estrogen-antagonistic region of raloxifene is characterized by a piperidine side chain. The orthogonal orientation of this basic side chain may contribute to raloxifene’s lack of uterotrophic effects. Replacement of the 6-hydroxy substituent with various functional groups has resulted in a reduction in cholesterol-lowering effect and antiproliferative action, whereas substitution of the 4’-hydroxy group with small electronegative substituents did not change the in vivo profile. Substitution of a larger group at the 4’position, however, resulted in increased uterine stimulation. Several raloxifene analogues are under investigation for their potential applications in a variety of diseases in which estrogen is thought to play a pathogenic role, such as uterine leiomyoma and endometriosis.[3]

Pharmacokinetics

The pharmacokinetics of raloxifene hydrochloride were investigated in over 1500 women in clinical trials. Although most of the women were white and postmenopausal, interpatient variability of approximately 30% was observed.

Absorption

Raloxifene is rapidly absorbed from the gastrointestinal tract and undergoes extensive first pass glucuronidation. Approximately 60% of an oral dose is absorbed;however, because of extensive presystemic glucuronide conjugation, absolute bioavailability is only 2%. Significant interpatient differences in bioavailability may result from alterations in the rate of glucuronide formation and enterohepatic recycling. Administration of a single dose of 185 mg of raloxifene hydrochlorideto four healthy volunteers resulted in a maximum plasma concentration (Cmax) of 12.5 µg/L within 0.5 hour. The time to maximum concentration of raloxifene varies, depending on the conversion of the drug in the systemic circulation. Administration of the recommended 60-mg dose is expected to result in a mean peak Cmax of 0.5 ng/mL. Multiple doses of 60 mg are expected to produce a mean Cmax of 1.36 ng/mL. Although the area under the plasma concentration-versustime curve (AUC) does not change significantly when multiple doses are given, increasing the dose from 30 mg to 150 mg results in a slight increase in AUC. Administration of raloxifene with a high-fat meal increases Cmax and AUC by 28% and 16%, respectively, although the effects are clinically insignificant. Therefore, raloxifene may be administered without regard to meals.

Distribution

Raloxifene is widelydistributed into tissues; the volumeof distribution (V) is 2348 L/kg afteradministration of a single oral dose of30–150 mg. V is not dose dependent. Studies with radioactively labeled raloxifene indicate extensive distribution into the liver, serum,lungs, and kidneys. Conversion of the drug to an active metabolite appears to occur in several tissues, including the liver, lungs, spleen, bone, uterus,and kidneys. Raloxifene and its conjugates are 95% bound to albumin and α1-acid glycoprotein in vitro.Raloxifene does not bind to sex steroid-binding globulin. Although it is unknown whether raloxifene is distributed into breast milk, its high protein-binding profile should theoretically limit such distribution. Nevertheless, lactating women should not use raloxifene. Raloxifene is a pregnancy category X drug and is therefore contraindicated in pregnant women.

Metabolism

Raloxifene undergoes extensive first-pass metabolism. Conjugate formation includes raloxifene 4′-glucuronide,6-glucuronide, and 6,4′-diglucuronide. Very small amounts of free raloxifene (<1% of a dose) are detected in the circulation. The absence of other metabolites suggests that raloxifene is not metabolized by the cytochrome P-450 isoenzyme system. Although raloxifene may be converted back within certain tissues, reconversion to the parent compound does not appear to occur in major target organs, such as the uterus and skeleton. Therefore, it appears that the tissue selectivity of raloxifene is not explained by deconjugation of metabolites to the parent compound in different tissues. The terminal loglinear portions of plasma concentration curves for raloxifene and its conjugates are parallel. The clearance of raloxifene hydrochloride 400 mg/day given for five days to healthy premenopausal women was 51.5–128.3 L/hr/kg, depending on the phase of the menstrual cycle. A mean steady-state V of 4135 L/kg was observed for the women. There is no evidence to date to suggest significant influences of sex, race, or age (42–84 years) on the clearance of raloxifene. The half-life (t ½) of raloxifene at steady state ranges from 15.8 to 86.6 hours and averages 32.5 hours.16 One study evaluated the t ½ of raloxifene in 14 healthy postmenopausal women and 14 healthy men. The t ½ ranged from 11 to 27 hours. The oral clearance of a single dose of raloxifene is 44.1 L/ hr/kg. The t ½ of raloxifene may be prolonged to 27.7 hours, secondary to reverse systemic metabolism and enterohepatic recycling, when the drug is given on a long-term basis.

Elimination

Raloxifene is excreted primarily in the feces. Glucuronide metabolites are eliminated in the biliary tract, and are subsequently broken down by bacteria to the parent drug. Less than 0.2% of raloxifene is excreted unchanged in the urine; less than 6% is excreted in the urine as glucuronide conjugates.[1] 

References

[1] Snyder KR, Sparano N, Malinowski JM. Raloxifene hydrochloride. Am J Health Syst Pharm. 2000;57(18):1669-1678.

[2] Rang HP, Dale MM, Ritter JM, Moore PK, eds. In: Rang and Dale's Pharmacology. 7th ed. Edinburgh: Elsevier/Churchill Livingstone; 2012:438-439. ISBN:978-0-7020-3471-8.

[3] Khovidhunkit W, Shoback DM. Clinical effects of raloxifene hydrochloride in women. Ann Intern Med. 1999;130(5):431-439. doi:10.7326/0003-4819-130-5-199903020-00015

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