Received for publication November 15, 2005.
Revised March 21, 2006.
Accepted for publication March 21, 2006.

Saturable binding of indisulam to plasma proteins and distribution to human erythrocytes

Abstract

The anti-cancer agent indisulam has a non-linear pharmacokinetic profile, which may be partly related to saturable binding to blood constituents. To gain insight into the complex non-linear 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, 3) in erythrocyte membranes to investigate non-specific binding in erythrocytes. For in vivo assessment, 21 patients received 400-900mg/m² indisulam in a one- or two-hour 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 non-linear 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).

Key words: anticancer agents, drug disposition, physiologically-based modeling, plasma protein binding, protein binding