Author:

Keywords:

Antineoplastic Combined Chemotherapy Protocols, Chromatography, High Pressure Liquid, Deoxycytidine, Erythrocytes, Female, Humans, Male, Taxoids, Science & Technology, Life Sciences & Biomedicine, Oncology, Pharmacology & Pharmacy, docetaxel, erythrocyte, gemcitabine, partition ratio, plasma, red blood cell, PHASE-I, BINDING, PLASMA, CELLS, PHARMACOKINETICS, DRUGS, Docetaxel, In Vitro Techniques, Gemcitabine, 0304 Medicinal and Biomolecular Chemistry, 1101 Medical Biochemistry and Metabolomics, 1115 Pharmacology and Pharmaceutical Sciences, Oncology & Carcinogenesis, 3211 Oncology and carcinogenesis, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry

Abstract:

We have performed in vitro incubations of blood from male and female volunteers with gemcitabine and docetaxel alone, and in combination, at different concentration gradients in order to investigate changes in partition between red blood cells (RBCs), total plasma and the free fraction. After extraction and sample pre-treatment, a validated high-performance liquid chromatography method followed by UV detection was used to determine the concentrations of both drugs in the different blood constituents. The partition ratio [the concentration in the erythrocytes divided by the concentration in plasma (E/P)] was calculated. The partition ratio of docetaxel varied from 0.02 to 1.44 (mean 0.35), reflecting its relatively low affinity for RBCs, probably because of its high plasma protein binding (more than 98%). For gemcitabine, the partition ratio varied from 1 to 5, reflecting a high affinity for RBCs (less than 10% plasma protein bound). The partition ratios of both drugs increased significantly with higher whole-blood concentrations, favoring uptake in the erythrocytes when plasma protein binding is saturated. Combination incubations showed a complex and unexplained interaction between gender and the influence of docetaxel on the partition of gemcitabine. We conclude that the incorporation of drugs into the RBC pool may be important for transportation to tumor tissue and efficacy. In combination, one anti-cancer agent can alter the partition ratios of other anti-cancer agents.