Studies On The Pre-Clinical Pharmacokinetics Of Hydroxy-Camptothecin By Aerosol Inhalation Treating Lung Cancer

HCPT（10 - hydroxycamptothecin） is a indole alkalodis,which is isolated from camptotheca acuminate belonging Davidia involucrate plants.It is used for broad-spectrum anticancer drugs which causes tumor cell death damages by inhabiting DNA topoisomeraseⅠ.Currently,the quantitative analysisi of camptothecin drugs are mainly UV spectrophotometry,fluoro-spectrophotometry,HPLC,and so on.HCPT have carboxylic acid salts and lactone two forms,which are be transform in certain conditions.The domestic and international research show that L-HCPT is mainly active ingredient and C-HCPT is formulations for drug delivery（such as injection agent）.By searching related reports,we found that the quantitative analysisi of HCPT is mainly aim at alkaloids in the past research,only few about L-HCPT and C-HCPT separately was reported,the detection of L-HCPT and C-HCPT in blood and tissue by aerosol inhaling HCPT is still blank.Comparing aerosol inhaling and intravenous injecting HCPT,we study the concentration of L-HCPT and C-HCPT in blood and tissue to discuss dynamic change rules and provides the theory basisi for treating lung cancer in clinical aerosol inhalation.1.To establish HPLC-FLD determination of L-HCPT and C-HCPT in blood and tissue. Chromatographic conditions:column:Lichrospher C18 column（250 mm×4.6mm,5μm）,the pre-C18 column（10 mm×4.6 mm,5μm）;mobile phase:Ψ(acetonitrile:0.01 mol·L^-1 triethylamine buffer,pH7.4) = 32:68;flow rate:0.9 mL·min^-1;excitation wavelength:363 nm and emission wavelength:550 nm.The specificity,recovery,precision and stability all correspond to requirements and meet the different configuration of HCPT quantitative research needs.2.To study the pharmacokinetics of HCPT in guinea pigs’ blood.After aerosl inhaling and intravenous injecting,we determine the concentration of L-HCPT and C-HCPT in different time to discuss the dynamic change rules between L-HCPT and C-HCPT.From the parameters,we know that -HCPT and C-HCPT assume one compartment model in blood by inbreathing,and after intravenous injecting,L-HCPT is one compartment model, C-HCPT is two.The half-time of L-HCPT has no significant different between two drug delivery,but the half-time of C-HCPT is significantly lower than L-HCPT.Results show, the plasma bioavailability of aerosol drug is far lower than intravenous injection,so we know that the distribution of drug through blood to other organizations resulting in side effects may be far less than intravenous injection.By the concentration-time curve and the ration of early research finding available conclusion:No matter what administration,the structure of HCPT in blood is mainly C-HCPT.3.To study the pharmacokinetics of HCPT in the lung of guinea pigs.In aerosol drug delivery,the drug distributes from lung to blood and other organizations and is in elimination phase in the lung.And the drug is from blood to the organizations by intravenous injection.The lung tissue is absorbing in the first phase,and enter the elimination phase after reaching peak.Acorrding to the quantitative research of L-HCPT and O-HCPT,L-HCPT is mainly form in lung no matter what administration,and has clearly targeting.From parameters,L-HCPT assume two compartment model,its half-time is less lower intravenous injection which L-HCPT is one compartment model. Comparing concentration-time curve,we found the concentration of L-HCPT in 30 min is maintain a higher level,but is sharp decline after 30min.So it although extend the half-time of L-HCPT,could not prolong the role of drug time by intravenous injection.4 To study the pharmacokinetics of HCPT in the guinea pigs’ tissue.After the aerosol inhalation,the distribution of the lactone form of HCPT in the main organs（AUC） are: heart＞kidney＞lung＞stomach＞spleen＞liver＞intestinal.After intravenous injection, the distribution of the lactone form of HCPT in the main organs（AUC） are:kidney＞intestinal＞liver＞heart＞stomach＞lung＞spleen.From the concentration-time curve we know,the distribution of HCPT in main organs is mainly L-HCPT.Comparing two drug delivery,the concentration of L-HCPT in lung has greatest absorbable,and could keep high potency.Aerosol drug delivery can reduce other organization in the distribution of low toxicicty,could reduce side effects and has distinct advantages comparing to intraventous treatment of lung cancer.5.To improve the conventional aerosol inhalation method and the safety of the treatment of lung cancer were investigated on the HCPT,aerosol inhalation after the corresponding parts of the organization irritation response,the results indicate that in the experimental scope of reference,HCPT aerosol inhalation of the relevant organs without serious injury,in addition to the attention-induced inflammation,the method can be applied to practical applications.