title: 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.
authors.affiliation: Department of Clinical Oncology/Laboratory of Experimental Oncology, UZ Gasthuisberg, Leuven, Belgium. Herlinde.Dumez@uz.kuleuven.ac.be
authors.forename: Herlinde
authors.initials: H
authors.lastname: Dumez
authors.forename: Gunther
authors.initials: G
authors.lastname: Guetens
authors.forename: Gert
authors.initials: G
authors.lastname: De Boeck
authors.forename: Martin S
authors.initials: MS
authors.lastname: Highley
authors.forename: Ernst A
authors.initials: EA
authors.lastname: de Bruijn
authors.forename: Allan T
authors.initials: AT
authors.lastname: van Oosterom
authors.forename: Robert A A
authors.initials: RA
authors.lastname: Maes
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000097:blood* / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D000077146:Irinotecan; D008297:Male; D017678:Sex Distribution; D012907:Smoking / Q000009:adverse effects*; D013050:Spectrometry, Fluorescence; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin