In vitro pharmacokinetic study of the novel anticancer agent E7070: red blood cell and plasma protein binding in human blood
| Autor: | J. H. M. Schellens, R. C. A. M. Van Waardenburg, M. Ravic, J. H. Beijnen, Dick Pluim, H. J. G. D. Van Den Bongard |
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| Přispěvatelé: | Academic Medical Center |
| Rok vydání: | 2003 |
| Předmět: |
Pharmacology
Sulfonamides Cancer Research education.field_of_study Erythrocytes Chemistry Population Antineoplastic Agents Blood Proteins Plasma protein binding Blood proteins In vitro Red blood cell medicine.anatomical_structure Oncology Pharmacokinetics medicine Humans Distribution (pharmacology) Pharmacology (medical) education Whole blood |
| Zdroj: | Anti-cancer drugs, 14(6), 405-410. Lippincott Williams and Wilkins |
| ISSN: | 0959-4973 |
| DOI: | 10.1097/00001813-200307000-00003 |
| Popis: | E7070 is a novel sulfonamide anticancer agent that arrests the G1/S phase of the cell cycle. Preclinical and phase I studies have demonstrated non-linear pharmacokinetics (PK) of the drug. A population PK analysis revealed that the human plasma concentration - time data were best described by a three-compartment model with non-linear distribution. We have studied the in vitro interaction of 14C-radiolabeled E7070 with red blood cells (RBC) and its binding to plasma proteins in the concentration range where non-linearity in disposition was observed in humans to get more insight into the behavior of the drug. After the addition of E7070 to whole blood at 37°C, the drug is taken up or binds to RBC in a concentration-dependent manner. The addition of sodium azide, however, did not result in a decrease of drug uptake by RBC, indicating passive diffusion processes. A non-linear increase in drug uptake was observed at incubation concentrations above 4 μg/ml E7070 in whole blood. This non-linearity was confirmed by lower partition coefficients between RBC and plasma at higher incubation concentrations (from 2.37 at 4 μg/ml to 0.31 at 200 μg/ml). The plasma protein binding of E7070 was high (98-99%) and linear in the concentration range studied (20-200 μg/ml). In conclusion, E7070 in whole blood is preferentially bound to RBC and exhibits high plasma protein binding. The non-linear distribution of E7070 in humans can be caused, in part at least, by saturable binding of E7070 to RBC. © 2003 Lippincott Williams & Wilkins. |
| Databáze: | OpenAIRE |
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