Red blood cells: a neglected compartment in topotecan pharmacokinetic analysis

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Abstract
Previously, a gender dependency of topotecan was found in the pharmacokinetics in the plasma compartment. Here, we prospectively studied the red blood cell (RBC) partitioning of topotecan and evaluated its consequences for overall drug disposition. Blood samples were obtained from 12 patients receiving cisplatin followed by i.v. topotecan. Topotecan pharmacokinetic analysis was performed in whole blood, plasma and RBCs. Significantly slower clearance was noted in females (n=7) compared to males (n=5) for lactone and total topotecan in plasma (p<0.0001), and for total drug in RBCs (p=0.027), but not in whole blood. In addition, no gender-dependent differences were observed in the terminal half-lives of topotecan in any of the compartments. The area under the curve ratios for RBC total to plasma lactone were 2.53±0.0640 and 2.13±0.442 in males and females, respectively. Hence, topotecan displays preferential affinity for RBCs compared to plasma, although these cells do not act as a depot in which drug accumulates over time. RBCs thus play a principal role in the distribution kinetics of topotecan and have a major impact on its plasma pharmacokinetics. The data warrant a change from current practice in pharmacokinetic studies with this agent and provide further evidence that, in general, the choice of the appropriate assay matrix should be rationally based.