title: Pharmacokinetics, tissue distribution, and the lactone/carboxylate equilibrium of hydroxycamptothecin delivered via aerosol in mice.
abstract: Aerosol delivery is a route which is advantageous to the therapy of pulmonary diseases, such as lung cancer. The pharmacokinetics and tissue distribution after aerosol delivery of carboxylate form of hydroxycamptothecin (C-HCPT) were investigated. The concentrations of the three different types (lactone, carboxylate and the total of both forms) of HCPT were measured by HPLC analysis. The initial experiment showed no evident difference between lactone and carboxylate in the lungs during the aerosol treatment, compared with the HCPT content in plasma. The AUC(inf) value of lactone in the lungs was higher than that of carboxylate, which was 138,176.00 min ng g⁻¹ and 128,460.00 min ng g⁻¹, respectively. Meanwhile, AUC(inf) in the plasma during the entire treatment indicated that the lactone content was always at a lower level, and the carboxylate form tended to predominate, as shown by the lactone/carboxylate (L/C) equilibrium. The tissue distribution results showed that the lactone proportion in the liver increased up to the maximum value of 69.69% after aerosol administration, whereas the mean L/C equilibrium index for the liver was 2.07±1.06, and the C(max) and AUC(0-∞) values of the total HCPT were highest in the tissues. Based on these results we speculated that the initial wholly carboxylate form of the HCPT atomized liquid did not influence the transformation to lactone form. Moreover, the deposition of the total HCPT and lactone was higher in the lungs and other tissues than in the plasma after the aerosol treatment. This study will be beneficial to the therapy of pulmonary carcinoma.
authors.affiliation: Department of Pharmacy, Affiliated Drum Tower Hospital of Nanjing University, Nanjing 210008, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Wenjin
authors.initials: W
authors.lastname: Hu
authors.forename: Yun
authors.initials: Y
authors.lastname: Fang
authors.forename: Wenjie
authors.initials: W
authors.lastname: Hou
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D002264:Carboxylic Acids / Q000378:metabolism*; D005260:Female; D007783:Lactones / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D014018:Tissue Distribution
chemical_list: D000336:Aerosols; D002264:Carboxylic Acids; D007783:Lactones; D002166:Camptothecin