Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


osu1085168433.pdf (544.94 KB)

ETD Abstract Container

Abstract Header

Preclinical pharmacokinetics and skeletal pharmacology of a selective androgen receptor modulator

Kearbey, Jeffrey D.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1085168433

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Pharmacy.
Osteoporosis poses a significant health threat to the elderly population. The lifetime risk for hip, spine, and distal forearm fractures are 40% and 13% in women and men, respectively. As the longevity of the population increases, it becomes increasingly important to develop appropriate treatments to prevent fractures and/or promote healing. Androgens play a pivotal role in bone biology. However, side effect profiles and poor bioavailability limit the application of currently available androgen formulations. The discovery of nonsteroidal selective androgen receptor modulators (SARM) provides a unique opportunity to more clearly define the role of androgens in the skeleton and develop new therapeutic entities for the treatment of osteoporosis. We hypothesized that S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (S-4) would exert a protective and proliferative effect on the skeleton. Pharmacokinetic analysis of S-4 showed complete bioavailability, short time to peak plasma concentration, and relatively slow metabolic clearance at doses capable of eliciting maximal pharmacologic effect in rats. In a rat model of accelerated bone loss, our studies clearly showed that indices of bone density and bone quality were modulated by a nonsteroidal SARM. S-4 fully restored whole body bone mineral density (BMD), lumbar vertebrae BMD, femoral BMD, cortical content, and biomechanical strength in ovariectomized animals. These data suggest that S-4 could provide a novel pharmacological intervention in the prevention of bone loss in postmenopausal women. In an osteopenic rat model, S-4 fully restored whole body BMD in animals receiving > 0.1 mg/day S-4. Regional analysis of the L5-L6 vertebra and the femur by dual energy x-ray absorptiometry showed that S-4 completely restored BMD. BMD measured by peripheral computed tomography and biomechanical strength testing of the femur further supports our conclusion that S-4 is anabolic in bone. Our data suggest that S-4 is likely to significantly reduce the fracture risk in patients with osteoporosis through direct anabolic action on both muscle and bone. As S-4 is anabolic in bone, orally bioavailable, tissue-selective, and does not cross-react with other steroid hormone receptors, it offers significant advantages over currently available therapies for osteoporosis.
James Dalton (Advisor)
162 p.
Pharmacokinetics; Osteoporosis; Androgen; Selective androgen receptor modulator

Recommended Citations

Citations

  • Kearbey, J. D. (2004). Preclinical pharmacokinetics and skeletal pharmacology of a selective androgen receptor modulator [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1085168433

    APA Style (7th edition)

  • Kearbey, Jeffrey. Preclinical pharmacokinetics and skeletal pharmacology of a selective androgen receptor modulator. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1085168433.

    MLA Style (8th edition)

  • Kearbey, Jeffrey. "Preclinical pharmacokinetics and skeletal pharmacology of a selective androgen receptor modulator." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1085168433

    Chicago Manual of Style (17th edition)

osu1085168433
1,359
© 2004, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.