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- Title
Clinical pharmacokinetics, pharmacodynamics and metabolism of the novel matrix metalloproteinase inhibitor ABT-518.
- Authors
Crul, Mirjam; Beerepoot, Laurens V.; Stokvis, Ellen; Vermaat, Johannes S.; Rosing, Hilde; Beijnen, Jos H.; Voest, Emile E.; Schellens, Jan H.
- Abstract
Purpose. To investigate the pharmacokinetics, pharmacodynamics and metabolism of the novel matrix metalloproteinase (MMP) inhibitor ABT-518. Methods. Plasma and urine samples were obtained from six patients included in a phase I trial in which ABT-518 was given once daily via the oral route. Samples were analyzed by LC-MS/MS, ELISA and immunocapture assay. The pharmacokinetics of the parent compound and of detectable metabolites were calculated. Results. After a single dose of ABT-518 peak plasma levels were reached within 4–8 h. ABT-518 had an estimated clearance (Cl/F) of approximately 3 l/h, an estimated volume of distribution (V/F) of over 70 l and a terminal half-life (T1/2) of 20 h. At least six different metabolites were formed. Pharmacodynamic analysis for angiogenic growth factors (bFGF and VEGF) showed plasma and urine levels in the picogram range and for total MMP-9 and MMP-2 or MMP-9 activity showed plasma and urine levels in the nanogram range. Conclusions. The MMP inhibitor ABT-518 is extensively metabolized in humans. No significant correlations between pharmacokinetics and pharmacodynamics could be established.
- Subjects
PHARMACOKINETICS; PHARMACODYNAMICS; METABOLISM; METALLOPROTEINASES; BLOOD plasma; METABOLITES
- Publication
Cancer Chemotherapy & Pharmacology, 2002, Vol 50, Issue 6, p473
- ISSN
0344-5704
- Publication type
Article
- DOI
10.1007/s00280-002-0515-6