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


CONCLUSIONS
No undue tissue accumulation of TR and of bortezomib was observed in rats following a full clinical dosing cycle of bortezomib.
Hemeryck
Alex
A
Global Preclinical Development, Johnson & Johnson Pharmaceutical Research & Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium. ahemeryc@prdbe.jnj.com
Geerts
Rita
R
Monbaliu
Johan
J
Hassler
Stephan
S
Verhaeghe
Tom
T
Diels
Luc
L
Verluyten
Willy
W
van Beijsterveldt
Ludy
L
Mamidi
Rao N V S
RN
Janssen
Cor
C
De Coster
Roland
R
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001345:Autoradiography; D001897:Boronic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000069286:Bortezomib; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D004334:Drug Administration Schedule; D007275:Injections, Intravenous; D008297:Male; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011719:Pyrazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012588:Scintillation Counting; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D001897:Boronic Acids; D002250:Carbon Radioisotopes; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib