Tissue distribution and depletion kinetics of bortezomib and bortezomib-related radioactivity in male rats after single and repeated intravenous injection of 14C-bortezomib

Hemeryck, Alex; Geerts, R; Monbaliu, Johan; Hassler, Stephan; Verhaeghe, Tom; Diels, Luc; Verluyten, Willy L. M.; Beijsterveldt, Ludy van; Mamidi, Rao N. V. S.; Janssen, Cornelus G. M.; Coster, R. De

doi:10.1007/s00280-007-0424-9

Cited by 52 publications

(43 citation statements)

References 11 publications

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“…The clearance is more rapid than that reported for bortezomib in preclinical and clinical models (Papandreou et al, 2004;Hemeryck et al, 2007). Furthermore, plasma clearance at all of the dose levels was much higher than the reported hepatic blood flow for rats [55 ml/ (min ⅐ kg)] (Davies and Morris, 1993), suggesting that, unlike bortezomib, carfilzomib clearance is mediated largely by extrahepatic mechanisms.…”

Section: Discussionmentioning

confidence: 44%

Pharmacokinetics, Pharmacodynamics, Metabolism, Distribution, and Excretion of Carfilzomib in Rats

Jiao¹,

Wang²,

Fang³

et al. 2011

Drug Metab Dispos

115

111

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Section: Discussionmentioning

confidence: 44%

Pharmacokinetics, Pharmacodynamics, Metabolism, Distribution, and Excretion of Carfilzomib in Rats

Jiao¹,

Wang²,

Fang³

et al. 2011

Drug Metab Dispos

115

111

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“…54 In the latter 2, however, expression seems to be related to specific disease states leading to production of inflammatory cytokines known to induce 20S i subunits, suggesting that under normal conditions these would predominantly contain 20S. Moreover, peptide-based drugs such as bortezomib do not pass through the blood-brain barrier, 55 implying that central nervous system toxicity would be unlikely with IPSIs as well. This leaves intestinal epithelium as an area of concern for toxicity based on the known expression profiles, but our studies of cell lines derived from such tissues ( Figure S3) showed a predominant expression of 20S.…”

Section: Discussionmentioning

confidence: 99%

Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors

Kuhn

Hunsucker

Chen

et al. 2009

Blood

188

178

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Proteasome inhibition is a validated strategy for therapy of multiple myeloma, but this disease remains challenging as relapses are common, and often associated with increasing chemoresistance. Moreover, nonspecific proteasome inhibitors such as bortezomib can induce peripheral neuropathy and other toxicities that may compromise the ability to deliver therapy at full doses, thereby decreasing efficacy. One novel approach may be to target the immunoproteasome, a proteasomal variant found predominantly in cells of hematopoietic origin that differs from the constitutive proteasome found in most other cell types. Using purified preparations of constitutive and immunoproteasomes, we screened a rationally designed series of peptidyl-aldehydes and identified several with relative specificity for the immunoproteasome. The most potent immunoproteasome-specific inhibitor, IPSI-001, preferentially targeted the ␤1 i subunit of the immunoproteasome in vitro and in cellulo in a dose-dependent manner. This agent induced accumulation of ubiquitin-protein conjugates, proapoptotic proteins, and activated caspasemediated apoptosis. IPSI-001 potently inhibited proliferation in myeloma patient samples and other hematologic malignancies. Importantly, IPSI-001 was able to overcome conventional and novel drug resistance, including resistance to bortezomib. These findings provide a rationale for the translation of IPSIs to the clinic, where they may provide antimyeloma activity with greater specificity and less toxicity than current inhibitors.

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“…Two weekly doses of 0.2 mg/kg bortezomib solution were administered s.c., which is considered the highest dose to use without having increased mortality rates or severe side effects in rats (10,25,26). Control and EAMG groups were subdivided into three treatment regimes each (Table I).…”

Section: Experimental Design and Administration Of Drugsmentioning

confidence: 99%

“…The proteasome inhibitor bortezomib, also known under the trade name Velcade, is a boronic acid dipeptide (phenylalanine-leucine) derivative, which binds reversibly to the 26S proteasome (9). After injection, bortezomib is distributed widely and quickly to the blood and most tissues (10). Currently, bortezomib is approved for the treatment of multiple myeloma and mantle cell lymphoma.…”

mentioning

confidence: 99%

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Gomez

Vrolix

Martínez‐Martínez

et al. 2011

The Journal of Immunology

122

100

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Bortezomib, an inhibitor of proteasomes, has been reported to reduce autoantibody titers and to improve clinical condition in mice suffering from lupus-like disease. Bortezomib depletes both short- and long-lived plasma cells; the latter normally survive the standard immunosuppressant treatments targeting T and B cells. These findings encouraged us to test whether bortezomib is effective for alleviating the symptoms in the experimental autoimmune myasthenia gravis (EAMG) model for myasthenia gravis, a disease that is characterized by autoantibodies against the acetylcholine receptor (AChR) of skeletal muscle. Lewis rats were immunized with saline (control, n = 36) or Torpedo AChR (EAMG, n = 54) in CFA in the first week of an experimental period of 8 wk. After immunization, rats received twice a week s.c. injections of bortezomib (0.2 mg/kg in saline) or saline injections. Bortezomib induced apoptosis in bone marrow cells and reduced the amount of plasma cells in the bone marrow by up to 81%. In the EAMG animals, bortezomib efficiently reduced the rise of anti-AChR autoantibody titers, prevented ultrastructural damage of the postsynaptic membrane, improved neuromuscular transmission, and decreased myasthenic symptoms. This study thus underscores the potential of the therapeutic use of proteasome inhibitors to target plasma cells in Ab-mediated autoimmune diseases.

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Tissue distribution and depletion kinetics of bortezomib and bortezomib-related radioactivity in male rats after single and repeated intravenous injection of 14C-bortezomib

Abstract: No undue tissue accumulation of TR and of bortezomib was observed in rats following a full clinical dosing cycle of bortezomib.

Cited by 52 publications

References 11 publications

Pharmacokinetics, Pharmacodynamics, Metabolism, Distribution, and Excretion of Carfilzomib in Rats

Pharmacokinetics, Pharmacodynamics, Metabolism, Distribution, and Excretion of Carfilzomib in Rats

Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

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