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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

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Abstract

Purpose

The body distribution of total radioactivity (TR) and bortezomib was investigated in male Sprague-Dawley rats after single and repeated i.v. (bolus) administration with 14C-labelled bortezomib (VELCADE®) (0.2 mg/kg; 0.28 MBq./kg).

Methods

Bortezomib was dosed on days 1, 4, 8, and 11 (i.e. a clinical dosing cycle) and the animals were sacrificed at selected time points following single and repeated dose administration for the quantification of TR in blood, plasma, and various tissues by liquid scintillation counting following organ dissection or by quantitative whole body autoradiography. In selected tissues, bortezomib levels were determined by LC-MS/MS.

Results

In general, plasma TR levels were less than 10% of the corresponding blood concentrations. TR was rapidly and widely distributed to the tissues with only limited penetration into the central nervous system (CNS). In the tissues, highest levels of TR were measured in bortezomib-eliminating organs (liver and kidney), lymphoid tissues, and regions of rapidly dividing cells (e.g. the bone marrow, intestinal mucosa). Low TR concentrations were found in the CNS (tissue-to-blood ratio of ∼0.05 after repeated dosing). With the exception of the liver, TR consisted almost exclusively of the parent drug. Tissue concentrations of TR and bortezomib increased up to about threefold from the first to the third dose administration, after which they remained constant.

Conclusion

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

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Abbreviations

AUC:

Area under the concentration–time curve

C max :

Maximum concentration

CNS:

Central nervous system

UD:

Unchanged drug

LC-MS/MS:

Liquid chromatography coupled with tandem mass spectrometry

LSC:

Liquid scintillation counting

LLOQ:

Lower limit of quantification

QC:

Quality control

QWBA:

Quantitative whole body autoradiography

T/B:

Tissue-to-blood ratio

TR:

Total radioactivity

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Acknowledgments

The authors would also like to express their gratitude to Willem Meuldermans (J&JPRD), Gerald Miwa, and Li Yu (Millennium Pharmaceuticals) for reviewing the manuscript. Larry Weaner and David Hoerr (J&JPRD) are acknowledged for synthesizing 14C-bortezomib. Helena Geys is thanked for her contribution to the data analysis and Mia Vanthienen is acknowledged for secretarial assistance.

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Authors and Affiliations

  1. Global Preclinical Development, Johnson & Johnson Pharmaceutical Research & Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium

    Alex Hemeryck, Rita Geerts, Johan Monbaliu, Tom Verhaeghe, Luc Diels, Willy Verluyten, Ludy van Beijsterveldt, Cor Janssen & Roland De Coster

  2. Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA

    Rao N. V. S. Mamidi

  3. Environmental Chemistry and Pharmanalytics Division, RCC Ltd, Itingen, Switzerland

    Stephan Hassler

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  1. Alex Hemeryck
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Correspondence to Alex Hemeryck.

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Hemeryck, A., Geerts, R., Monbaliu, J. et al. Tissue distribution and depletion kinetics of bortezomib and bortezomib-related radioactivity in male rats after single and repeated intravenous injection of 14C-bortezomib. Cancer Chemother Pharmacol 60, 777–787 (2007). https://doi.org/10.1007/s00280-007-0424-9

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  • DOI: https://doi.org/10.1007/s00280-007-0424-9

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