QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.105.008326v1 34/6/1041    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zandvliet, A. S. Articles by Huitema, A. D. R. Search for Related Content PubMed PubMed Citation Articles by Zandvliet, A. S. Articles by Huitema, A. D. R.

SATURABLE BINDING OF INDISULAM TO PLASMA PROTEINS AND DISTRIBUTION TO HUMAN ERYTHROCYTES

Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands (A.S.Z., J.H.B., A.D.R.H.); Eisai Ltd., London, United Kingdom (W.C.); Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands (J.H.M.S.); and Department of Biomedical Analysis, Section of Drug Toxicology, Utrecht University, Utrecht, The Netherlands (J.H.M.S., J.H.B.)

The anticancer agent indisulam has a nonlinear pharmacokinetic profile, which may be partly related to saturable binding to blood constituents. To gain insight into the complex nonlinear behavior of indisulam, we investigated binding to plasma proteins and erythrocytes. The purpose of the study was to develop a physiological model for the distribution of indisulam in blood. Concentrations of radiolabeled indisulam were measured in vitro 1) in total plasma and in ultrafiltrate to investigate plasma protein binding, 2) in erythrocytes and in plasma to investigate distribution to erythrocytes, and 3) in erythrocyte membranes to investigate nonspecific binding in erythrocytes. For in vivo assessment, 21 patients received 400 to 900 mg/m² indisulam in a 1- or 2-h infusion. Total and free concentrations in plasma and concentrations in erythrocytes were determined at multiple time points. In vitro plasma protein binding was described by a Langmuir model with a maximal binding capacity (B_max = 767 µM) and an equilibrium dissociation constant (K_D = 1.02 µM). The maximal capacity of plasma protein binding in vivo corresponded to albumin levels. The bound concentration in erythrocytes was described by a two-site model, comprising a saturable and a nonspecific binding component. The saturable component (B_max = 174 µM) may correspond to binding to carbonic anhydrase. The physiological model adequately described the nonlinear disposition of indisulam in whole blood. Indisulam was bound to plasma proteins and distributed to erythrocytes in a saturable manner. These saturable processes may be attributed to binding to albumin (in plasma) and to carbonic anhydrase (in erythrocytes).