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General Description:

Lasofoxifene, identified by CAS number 180916-16-9, is a notable compound with significant therapeutic applications. Lasofoxifene is a non-steroidal 3rd generation selective estrogen receptor modulator (SERM) that selectively binds to both ERα and ERβ with high affinity. It is a naphthalene derivative marketed for prevention and treatment of osteoporosis and for the treatment of vaginal atrophy. It was initially developed as Oporia by Pfizer as a treatment for postmenopausal osteoporosis and vaginal atrophy, in which were both rejected for approval by FDA. Later Fablyn was developed as a result of a research collaboration between Pfizer and Ligand Pharmaceuticals with a newly submitted New Drug Application in 2008. It gained approval by European Commission in March 2009. Ligand Pharmaceuticals signed a license agreement with Sermonix Pharmaceuticals for the development and commercialization of oral lasofoxifene in the USA.

Indications:

This drug is primarily indicated for: Investigated for use/treatment in postmenopausal osteoporosis to reduce the risk of both vertebral and novertebral fractures, as well as address other postmenopausal conditions, including reduction in risk of breast cancer and treatment of vulvar and vaginal atrophy (VVA). Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Lasofoxifene undergoes metabolic processing primarily in: Phase I oxidation via hepatic CYP3A4/CYP3A5 and CYP2D6 accounts for nearly half of total metabolism of lasofoxifene. Phase II conjugation reactions include glucuronidation and sulfation. Its glucuronidation is catalyzed by UGTs that are expressed in both the liver (UGT1A1, UGT1A3, UGT1A6, and UGT1A9) and the intestine (UGT1A8 and UGT1A10). Further metabolites of lasofoxifene detected in plasma are the glucuronide of a hydroxylated metabolite, and the methylated catechols . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Lasofoxifene are crucial for its therapeutic efficacy: Peak plasma concentrations (Cmax) were reached in about 6.0 to 7.3 hours . Displays higher oral bioavailability compared to other SERMs with increased resistance to intestinal glucuronidation due to nonpolar tetrahydronaphthalene structure . In a comparative study in the rat, lasofoxifene showed bioavailability of 62% . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Lasofoxifene is an important consideration for its dosing schedule: Elimination half-life is approximately 6 days . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Lasofoxifene exhibits a strong affinity for binding with plasma proteins: Lasofoxifene is highly bound to plasma proteins (>99%) where it predominantly binds to albumin and α1-acid glycoprotein . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Lasofoxifene from the body primarily occurs through: Primarily fecal excretion and secondarily renal elimination as mainly metabolites, with less than 2% excreted in urine as unchanged parent drug. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Lasofoxifene is distributed throughout the body with a volume of distribution of: The apparent volume of distribution in postmenopausal women is 1350L . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Lasofoxifene is a critical factor in determining its safe and effective dosage: The apparent oral clearance (CL/F) of lasofoxifene in postmenopausal women is approximately 6.6 l/hr. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Lasofoxifene exerts its therapeutic effects through: Lasofoxifene exhibits both significant estrogenic and antiestrogenic activity both in vitro and in vivo, targeting any tissues that possess ERs, such as bone, uterus, breast, blood vessels, and liver. Binding assays demonstrated high affinity of the compound for both ERα and ERβ in a tissue-dependent manner. It mimics the effects of estradiol with varying agonist and antagonist effects. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Lasofoxifene functions by: Lasofoxifene mediates an agonist effect on estrogen receptors expressed on bone to mimic the positive effects of estrogen to reduce the production and lifespan of osteoclasts via altering the NF-kappaB ligand (RANKL)/RANK/osteoprotegerin system, stimulation of osteoblast (the bone forming cells) activity and additional effects on calcium homeostasis . It acts as an antagonist at uterus and mammary glands by suppressing the estrogen signaling in oncogenic pathways and inhibits the downstream gene transcription . A study also suggests that lasofoxifene may also act as an inverse agonist at CB2 cannabinoid receptor which is expressed in bone to inhibit osteoclast formation and resorptive activity. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Lasofoxifene belongs to the class of organic compounds known as phenylnaphthalenes. These are compounds containing a phenylnaphthalene skeleton, which consists of a naphthalene bound to a phenyl group, classified under the direct parent group Phenylnaphthalenes. This compound is a part of the Organic compounds, falling under the Benzenoids superclass, and categorized within the Naphthalenes class, specifically within the Phenylnaphthalenes subclass.

Categories:

Lasofoxifene is categorized under the following therapeutic classes: Genito Urinary System and Sex Hormones, Naphthalenes, Selective Estrogen Receptor Modulators, Sex Hormones and Modulators of the Genital System. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.