Metabolism, Distribution, and Excretion of a Next Generation Selective Estrogen Receptor Modulator, Lasofoxifene, in Rats and Monkeys

Prakash, Chandra; Johnson, Kim A.; Schroeder, Clinton M.; Potchoiba, Michael J.

doi:10.1124/dmd.108.021808

Cited by 14 publications

(11 citation statements)

References 35 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly lasofoxifene creates a very interesting innovation in enhanced pharmacokinetics. Lasofoxifene is extensively metabolized in rats and monkeys with tissues achieving maximal concentrations within one hour of oral administration of 14 C labeled lasofoxifene [53]. There was greater than 95% of lasofoxifene and metabolites excreted in feces through the biliary route with only a small amount of glucoronide.…”

Section: Pharmacokinetics Of Tamoxifen and Raloxifenementioning

confidence: 99%

The Discovery and Development of Selective Estrogen Receptor Modulators (SERMs) for Clinical Practice

Maximov¹,

Lee²,

Jordan³

2013

CCP

319

255

View full text Add to dashboard Cite

Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists or antagonists. These drugs have been intensively studied over the past decade and have proven to be a highly versatile group for the treatment of different conditions associated with postmenopausal women’s health, including hormone responsive cancer and osteoporosis. Tamoxifen, a failed contraceptive is currently used to treat all stages of breast cancer, chemoprevention in women at high risk for breast cancer and also has beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene, a failed breast cancer drug, is the only SERM approved internationally for the prevention and treatment of postmenopausal osteoporosis and vertebral fractures. However, although these SERMs have many benefits, they also have some potentially serious adverse effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These adverse effects represent a major concern given that long-term therapy is required to prevent osteoporosis or prevent and treat breast cancer.The search for the ‘ideal’ SERM, which would have estrogenic effects on bone and serum lipids, neutral effects on the uterus, and antiestrogenic effects on breast tissue, but none of the adverse effects associated with current therapies, is currently under way. Ospemifene, lasofoxifene, bazedoxifene and arzoxifene, which are new SERM molecules with potentially greater efficacy and potency than previous SERMs, have been investigated for use in the treatment and prevention of osteoporosis. These drugs have been shown to be comparably effective to conventional hormone replacement therapy in animal models, with potential indications for an improved safety profile. Clinical efficacy data from ongoing phase III trials are available or are awaited for each SERM so that a true understanding of the therapeutic potential of these compounds can be obtained.In this article, we describe the discovery and development of the group of medicines called SERMs. The newer SERMs in late development: ospemifene, lasofoxifene, bazedoxifene, are arzoxifene are described in detail.

show abstract

Section: Pharmacokinetics Of Tamoxifen and Raloxifenementioning

confidence: 99%

The Discovery and Development of Selective Estrogen Receptor Modulators (SERMs) for Clinical Practice

Maximov¹,

Lee²,

Jordan³

2013

CCP

319

255

View full text Add to dashboard Cite

show abstract

“… Ion chromatograms of independently characterized glucuronides before and after treatment with aqueous hydroxylamine as described. (a) Mouse urine extract showing the phenolic glucuronides (M3, M4, M7, and M24) of lasofoxifene 23. (b) Ion chromatogram ( m/z 317) of the glucuronide of compound Y.…”

Section: Resultsmentioning

confidence: 99%

“…In the development of lasofoxifene, definitive metabolic studies using radiolabeled drug showed several urinary phenolic glucuronides. 23 Mouse urine from a 14 C-labeled lasofoxifene mass balance study was used to examine the reactivity with hydroxylamine.…”

Section: Lasofoxifene Glucuronidesmentioning

confidence: 99%

A rapid and specific derivatization procedure to identify acyl‐glucuronides by mass spectrometry

Vaz¹,

Wang²,

Bessire³

et al. 2010

Rapid Comm Mass Spectrometry

View full text Add to dashboard Cite

A simple procedure is described to identify acyl-glucuronides by coupled liquid chromatography/mass spectrometry after derivatization to a hydroxamic acid with hydroxylamine. The reaction specificity obviates the need for isolation of the acyl-glucuronide from an extract. Glucuronides derived from carbamic acids, and alkyl- and aromatic amines, are inert to the derivatization reaction conditions, making the hydroxamic acid derivative a fingerprint for acyl-glucuronides.

show abstract

“…The extent of absorption of lasofoxifene was investigated in the intact and bile-duct rats after oral administration of single dose of [ 14 C]lasofoxifene [121]. The cumulative excretion amounted to 1.72% in the urine and 95.0% in the feces of intact rats.…”

Section: Absorptionmentioning

confidence: 99%

“…Prakash et al . [121] examined tissue distribution in male and female pigmented rats (Long-Evans) using WBAL following administration of a single oral dose of [ 14 C]lasofoxifene. [ 14 C]Lasofoxifene-related radioactivity distributed rapidly in the rat with most tissues achieving maximal concentrations at 1 h. Tissue exposure was similar in male and female rats, with the greatest exposure in the uvea.…”

Section: Distributionmentioning

confidence: 99%

ADMEProfiling in Drug Discovery and Development: An Overview

Bohnert

Prakash

2012

Encyclopedia of Drug Metabolism and Interactions

Self Cite

View full text Add to dashboard Cite

The applications of parallel synthesis and combinatory chemistry to expedite lead finding and lead optimization processes have shifted the chemical libraries toward poorer biopharmaceutical, ADME (absorption, distribution, metabolism, and excretion), and pharmacokinetic (PK) properties. A drug candidate should have desirable biopharmaceutical properties such as good solubility and good permeability, as well as optimal and ADME/PK properties. The early knowledge of liability of biopharmaceutical, ADME/PK, and DDI properties is very valuable in drug candidate selection process. In the last one decade, multiple in silico, in vitro, and in vivo ADME studies have been developed and implemented in the drug discovery and development process to alert chemists and drug metabolism scientists of the potential ADME, PK and DDI issues in the clinic. In this chapter, we attempt to discuss these various ADME profiling approaches in drug discovery and development process and the latest technologies of the selected assays.

show abstract

Metabolism, Distribution, and Excretion of a Next Generation Selective Estrogen Receptor Modulator, Lasofoxifene, in Rats and Monkeys

Cited by 14 publications

References 35 publications

The Discovery and Development of Selective Estrogen Receptor Modulators (SERMs) for Clinical Practice

The Discovery and Development of Selective Estrogen Receptor Modulators (SERMs) for Clinical Practice

A rapid and specific derivatization procedure to identify acyl‐glucuronides by mass spectrometry

ADMEProfiling in Drug Discovery and Development: An Overview

Contact Info

Product

Resources

About