Zotarolimus, a Novel Sirolimus Analogue With Potent Anti-proliferative Activity on Coronary Smooth Muscle Cells and Reduced Potential for Systemic Immunosuppression

Autor: Stevan W. Djuric, Kennan C. Marsh, Gin C. Hsieh, Michael P. Sheets, Yung-Wu Chen, Thomas A. Fey, Cindy Henry, Karl W. Mollison, Rolf Wagner, Donna M. Gauvin, George W. Carter, James M. Trevillyan, Teresa A. Rosenberg, Sandra E. Burke, Steve J. Ballaron, Joy Bauch, Morey L. Smith
Rok vydání: 2007
Předmět:
Graft Rejection
Male
Encephalomyelitis
Autoimmune
Experimental
T-Lymphocytes
medicine.medical_treatment
Myocytes
Smooth Muscle
Tacrolimus Binding Protein 1A
Pharmacology
Binding
Competitive
Drug Hypersensitivity
Rats
Sprague-Dawley
Inhibitory Concentration 50
Restenosis
In vivo
Rats
Inbred BN
Angioplasty
Animals
Humans
Medicine
Hypersensitivity
Delayed
Zotarolimus
cardiovascular diseases
PI3K/AKT/mTOR pathway
Cell Proliferation
Sirolimus
Dose-Response Relationship
Drug
biology
business.industry
equipment and supplies
medicine.disease
Coronary Vessels
Rats
Disease Models
Animal
surgical procedures
operative
Animals
Newborn
Rats
Inbred Lew
Concanavalin A
Allograft rejection
cardiovascular system
biology.protein
Heart Transplantation
Lymphocyte Culture Test
Mixed
Cardiology and Cardiovascular Medicine
business
Immunosuppressive Agents
Half-Life
medicine.drug
Zdroj: Journal of Cardiovascular Pharmacology. 49:228-235
ISSN: 0160-2446
DOI: 10.1097/fjc.0b013e3180325b0a
Popis: Sirolimus (rapamycin) is an immunosuppressant used in preventing allograft rejection and in drug-eluting stents to prevent restenosis after angioplasty. Zotarolimus, an analogue of sirolimus, was designed to have a shorter in vivo half-life. Zotarolimus was found to be mechanistically similar to sirolimus in having high-affinity binding to the immunophilin FKBP12 and comparable potency for inhibiting in vitro proliferation of both human and rat T cells. Rat pharmacokinetic studies with intravenous dosing demonstrated terminal elimination half-lives of 9.4 hours and 14.0 hours for zotarolimus and sirolimus, respectively. Given orally, T1/2 values were 7.9 hours and 33.4 hours, respectively. Consistent with its shorter duration, zotarolimus showed a corresponding and statistically significant 4-fold reduction in potency for systemic immunosuppression in 3 rat disease models. Pharmacokinetic studies in cynomolgus monkey underpredicted the half-life difference between zotarolimus and sirolimus apparent from recent clinical data. In vitro inhibition of human coronary artery smooth muscle cell proliferation by zotarolimus was comparable to sirolimus. Drug-eluting stents for local delivery of zotarolimus to the vessel wall of coronary arteries are in clinical development. The pharmacological profile of zotarolimus suggests it may be advantageous for preventing restenosis with a reduced potential for causing systemic immunosuppression or other side effects.
Databáze: OpenAIRE
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