In vitro partition of irinotecan (CPT-11) in human volunteer blood: the influence of concentration, gender and smoking

Abstract

We have performed in vitro incubations of blood from male and female volunteers, smokers and non-smokers, with irinotecan at a gradient of different concentrations in order to investigate changes of partition between red blood cells (RBCs), total plasma and the free fraction. Since irinotecan (CPT-11) is not metabolized in vitro, there is no data available on its active metabolite SN-38. After extraction and sample pre-treatment, a validated high-performance liquid chromatography method followed by fluorescence detection was used to determine the concentration of the drug 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 CPT-11 varied from 0.7 to 2.8, reflecting its relatively high affinity for the erythrocyte, probably because of its only moderate plasma protein binding (65%). The partition ratios increased significantly with higher whole-blood concentrations, favoring uptake in the erythrocytes when plasma protein binding is saturated. No gender difference was detected, but we found relatively more CPT-11 in the erythrocytes of non-smokers compared to smokers. The incorporation of drugs into the RBC pool may be important for transportation to tumor tissue and efficacy. Smoking can have a significant influence on drug partition in the blood.

UHPLC–MS/MS method for the quantification of ultra‐traces of irinotecan and its metabolites in red blood cells and plasma to detect caregivers' contamination

“…Combes et al have explained this distribution by a surface binding with different binding sites and affinities with blood cells 28 . The results of Dumez et al 27 are in agreement with most of our observations for which irinotecan is detected in more RBC samples than plasma ones (8/12 and 4/12, respectively). Only sample E deviates from this rule.…”

“…This study shows that the concentration of irinotecan is always higher than that of SN-38 in both plasma and RBC. Dumez et al 27 have in vitro exposed whole blood to irinotecan concentrations ranging from 5 ng/ml to 50 μg/ml for 1 h. The results show a preferential distribution of irinotecan toward RBC up to a factor of 2.8. These results are obtained for lower concentrations than in the de Jong et al study.…”

In Vivo Blood-Brain Barrier Transport of Oxycodone in the Rat: Indications for Active Influx and Implications for Pharmacokinetics/Pharmacodynamics

“…The RBCs were prepared according to a previously described method (Dumez et al, 2005). The RBCs were diluted with 4 times its volume with distilled water.…”

In Vitro and in Vivo Studies on Plasma-to-Blood Ratio of Paclitaxel in Human, Rabbit and Rat Blood Fractions

“…Additionally, the importance of the erythrocyte uptake of drugs and the influence of drug-drug combination on their erythrocyte-plasma partition ratios has also been recognized. [23][24][25][26] It was reported that erythrocytes formed secondary transport system for paclitaxel in whole blood (CrEL micelles act as the principal carrier of paclitaxel in the systemic circulation). 10) According to the rationale mentioned above, higher partition of paclitaxel binding to erythrocytes, meaning lower PBR values, would induce the reduction of free paclitaxel in plasma water phase in the absence of CrEL.…”