Abstract
Purpose: ABT-751 is an orally bioavailable sulfonamide that binds to the colchicine binding site on β-tubulin and inhibits microtubule polymerization. The plasma and cerebrospinal fluid (CSF) pharmacokinetics of ABT-751, after a short intravenous infusion, were evaluated in a non-human primate (Macaca mulatta) model that is highly predictive of the CSF penetration of drugs in humans. Materials and methods: Plasma and CSF samples were collected over 24 h after 7.5 mg/kg (150 mg/m2) ABT-751 infused over 0.25-0.70 h, and ABT-751 concentrations in plasma and CSF were quantified using a validated HPLC-MS/MS assay. Pharmacokinetic parameters in plasma and CSF were derived using non-compartmental methods. Results and conclusion: Plasma disappearance was bi-exponential with a terminal half-life of 13 h. The mean ± SD clearance was 100 ± 18 ml/min m2, the mean ± SD volume of distribution at steady state was 1.3 ± 0.5 l/kg, and the mean ± SD mean residence time was 4.6 ± 1.8 h. The mean ± SD peak ABT-751 concentration in CSF was 0.26 ± 0.08 μM, and the mean ± SD CSF half-life of 1.3 ± 0.3 h. CSF penetration was limited (mean ± SD AUCCSF:AUCplasma, 1.1 ± 0.3%) relative to total (protein-bound + free) plasma drug concentrations, but the CSF concentrations approximated the estimated free drug concentrations in plasma.
Original language | English (US) |
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Pages (from-to) | 563-567 |
Number of pages | 5 |
Journal | Cancer Chemotherapy and Pharmacology |
Volume | 60 |
Issue number | 4 |
DOIs | |
State | Published - Sep 2007 |
Externally published | Yes |
Keywords
- ABT-751
- Cerebrospinal fluid
- Microtubule
- Non-human primate
- Pharmacokinetics
- Tubulin
ASJC Scopus subject areas
- Oncology
- Toxicology
- Pharmacology
- Cancer Research
- Pharmacology (medical)