Disease relevance of Oporia

• Lasofoxifene decreased body weight in all dose groups compared with both sham and ORX control values [1].
• Similarly, no uterine hypertrophy was observed in aged (17-month-old) female rats treated (p.o.) with CP-336,156 at 10 or 100 microg/kg x day for 28 days [2].
• Proximal tibial and lumber vertebral trabecular bone histomorphometric analysis showed that all doses of lasofoxifene significantly reduced OVX-induced bone loss by decreasing bone resorption and bone turnover [3].
• These results suggest that SERMs such as lasofoxifene may be useful therapeutic agents for preventing bone loss in elderly men with some degree of hypogonadism [1].
• Digoxin is commonly prescribed for arrhythmias and congestive heart failure, has a narrow therapeutic index, and may be coadministered with lasofoxifene [4].

High impact information on Oporia

• The purpose of this study was to determine the long-term effects of lasofoxifene, a new selective estrogen receptor modulator, on bone mass, bone strength, and reproductive tissues in ovariectomized (OVX) rats [3].
• No abnormal finding associated with lasofoxifene was observed with uterine histology examination [3].
• Long-term treatment of lasofoxifene preserves bone mass and bone strength and does not adversely affect the uterus in ovariectomized rats [3].
• Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone loss induced by aging and orchidectomy in the adult rat [1].
• When given orally to immature (3-week-old) female Sprague-Dawley rats for 3 days at doses of 0.1, 1.0, 10, or 100 microg/kg x day, unlike 17alpha-ethynyl estradiol, CP-336,156 had no effect on uterine wet or dry weight [2].

Chemical compound and disease context of Oporia

• In 5-month-old ovariectomized (OVX) Sprague-Dawley female rats, CP-336,156 completely prevented OVX-induced increases in body weight gain, total serum cholesterol, and serum osteocalcin at doses between 10 and 1000 microg/kg x day after 4 weeks [2].

Biological context of Oporia

• CONCLUSIONS: These results demonstrated that lasofoxifene stimulated vaginal mucus formation without causing cell proliferation in the rat reproductive tract [5].
• This study compared the pharmacokinetics of 0.25 mg lasofoxifene in subjects with mild (Child-Pugh grade A, n = 6) or moderate (Child-Pugh grade B, n = 6) hepatic impairment and healthy volunteers (n = 6) [6].
• Lasofoxifene C(max) and AUC ratios (90% CI) with/without paroxetine were 118% (95.4, 146) and 135% (120, 152), respectively [7].
• Clinical pharmacology of lasofoxifene in Japanese and white postmenopausal women [8].
• Maternal milk and plasma were sampled for concentrations of lasofoxifene on Lactation Days 4, 7, and 14 [9].

Anatomical context of Oporia

• We also found that CP-336,156 decreased total serum cholesterol and fat body mass and had no effect on lean body mass in these aged female rats [2].
• RESULTS: Lasofoxifene and raloxifene showed a minimal increase in vaginal and uterine weight, epithelial cell proliferation, and epithelial thickness in comparison with estradiol and tamoxifen [5].
• Lasofoxifene-related teratologic findings were noted at 10 and 100 mg/kg and included imperforate anus with hypoplastic tails, dilatation of the ureters and renal pelvis, misaligned sternebrae, hypoflexion of hindpaw, wavy ribs, and absent ossification of sternebrae [10].

Associations of Oporia with other chemical compounds

• Least squares mean increases (95% CI) from baseline in lumbar spine BMD, compared with placebo, were 3.6% (1.9, 5.2) for lasofoxifene 0.25 mg/day, 3.9% (2.4, 5.5) for lasofoxifene 1.0 mg/day, and 1.7% (0.3, 3.0) for raloxifene [11].
• The second study enrolled 20 healthy postmenopausal women (10 per group) to compare the pharmacokinetics of a single dose of lasofoxifene (0.25 mg) alone and in combination with paroxetine (30 mg qd x 21 days) [7].
• METHODS: The first parallel group study was conducted in 45 healthy postmenopausal women (15 per group) to compare the pharmacokinetics of a single dose of lasofoxifene (0.25 mg) administered alone and in combination with ketoconazole (400 mg daily x 20 days) or fluconazole (400 mg daily x 20 days) [7].
• AIMS: Two studies were conduced to assess the effects of ketoconazole, a CYP3A4/5 inhibitor; fluconazole, a CYP2C9 inhibitor; and paroxetine, a CYP2D6 inhibitor, on lasofoxifene pharmacokinetics [7].
• AIM: To investigate the effect of steady-state lasofoxifene on the pharmacokinetics and pharmacodynamics of warfarin [12].

Gene context of Oporia

• CONCLUSIONS: Lasofoxifene has no effect on CYP2E1- or CYP2D6-mediated drug metabolism and should not affect drugs metabolized by other cytochrome P450 isoenzymes [13].
• Effects of steady-state lasofoxifene on CYP2D6- and CYP2E1-mediated metabolism [13].
• Lasofoxifene enhances vaginal mucus formation without causing hypertrophy and increases estrogen receptor beta and androgen receptor in rats [5].
• After E2, CP 336156 was the most efficacious in increasing PR mRNA with a maximal stimulation of 20% of E2 levels, while 4OHT stimulated only 17% [14].
• BACKGROUND: Lasofoxifene, a selective estrogen receptor modulator, may be coadministered with other drugs, raising the issue of drug-drug interactions [13].

Analytical, diagnostic and therapeutic context of Oporia

• These data showed that lasofoxifene prevented bone loss by inhibiting bone turnover associated with aging and orchidectomy in 10-month-old male rats [1].
• Careful attention to technical issues preceded successful crystallography of the ligand-binding domain of estrogen receptor alpha (ERalpha) complexed with CP-336156, a nonsteroidal estrogen agonist/antagonist [15].
• Although the decrease in PT/INR may not be clinically meaningful, more frequent INR monitoring may be considered during lasofoxifene introduction and discontinuation, consistent with warfarin's label [12].

References