title: Role of erythrocytes and serum proteins in the kinetic profile of total 9-amino-20(S)-camptothecin in humans.
abstract: 9-Amino-20(S)-camptothecin (9-AC) is a water-insoluble topoisomerase I inhibitor with evident schedule-dependent antitumor activity in preclinical studies. The pharmacokinetic behavior of 9-AC given as a bolus i.v. infusion (1.0 mg/m2 over 5 min) was recently characterized in 12 patients in a bioavailability study. Remarkable rebound concentrations of 9-AC total drug (i.e. lactone plus carboxylate forms) were observed at about 2-3 h after dosing. In vitro experiments indicated that this phenomenon was associated with a substantial uptake of 9-AC lactone by erythrocytes immediately after dosing and its subsequent release followed by accumulation of 9-AC carboxylate in the plasma compartment mediated by a pH-dependent hydrolysis of the lactone form, which is unable to diffuse across cell membranes. The preferential binding of 9-AC carboxylate to human serum albumin shifts the equilibrium between the lactone and carboxylate forms of 9-AC to the pharmacological inactive carboxylate form.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, The Netherlands. loos@ocnh.azr.nl
authors.forename: W J
authors.initials: WJ
authors.lastname: Loos
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: H J
authors.initials: HJ
authors.lastname: Gelderblom
authors.forename: M J
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: E
authors.initials: E
authors.lastname: Brouwer
authors.forename: B K
authors.initials: BK
authors.lastname: Dallaire
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D002522:Chlorocebus aethiops; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D051379:Mice; D013997:Time Factors; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured; D014709:Vero Cells
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; C080125:9-aminocamptothecin; D002166:Camptothecin