In vitro and in vivo methotrexate disposition in alveolar macrophages: comparison of pharmacokinetic parameters of two formulations.
MTX-liposomes, prepared with a polymerised core (LSP), were administered in anaesthetised rats by pulmonary instillation versus free drug. No toxicological effects were macroscopically observed. After each time point: 15, 30, 60 and 90 min, animals were humanely killed and analyses of radio-signal were done. This approach allowed recovery of MTX or breakdown products within biological samples. Previously, kinetics of MTX cellular uptake was performed to identify the cytotoxic concentration of drug formulation for human macrophage. Flow cytometry was set-up to characterise liposomal uptake by ex vivo pulmonary macrophage. Cells were isolated by bronchioloalveolar washes from animals. Results have shown clear different pharmacokinetic parameters between free MTX and the liposomal form of MTX. Unlike classical liposomes, which are mainly taken up by the reticulo-endothelial system, LSP-MTX was not targeted to spleen or kidney. The route of administration could be an explanation of this phenomenon. In addition, LSP-MTX was more retained by the lung tissue. Moreover, free form of the drug reaches easily lymph node. This latest result should be taken into consideration for neoplasic disease and more specifically when lymph nodes are a way for pulmonary metastasis. Finally, LSP-MTX should be tested in physio-pathological model of lung cancer to evaluate the influence of the variation of liposomal formulation pharmacokinetic parameters on the drug efficacy.
Doddoli
Christophe
C
Université de la Méditerranée (Aix-Marseille II), Faculté de Médecine: Services de chirurgie thoracique, Hôpital Sainte-Marguerite, Assistance Publique, Hôpitaux de Marseille, Marseille, France.
Ghez
Olivier
O
Barlési
Fabrice
F
D'journo
Benoit
B
Robitail
Stéphane
S
Thomas
Pascal
P
Clerc
Thierry
T
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005079:Excipients; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate; D007278:Injections, Spinal; D008081:Liposomes; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D005079:Excipients; D008081:Liposomes; D016650:Fluorescein-5-isothiocyanate; D008727:Methotrexate