Imatinib is an efficacious anticancer drug with a spectrum of potential antitumour applications limited by poor biodistribution at therapeutic concentrations to the tissues of interest.We assess the pharma-cokinetic a...Imatinib is an efficacious anticancer drug with a spectrum of potential antitumour applications limited by poor biodistribution at therapeutic concentrations to the tissues of interest.We assess the pharma-cokinetic and tissue distribution profile of imatinib in a liposome formulation.Its single dose(6.25 mg·kg-1) in a liposome formulation was administered iv to male mice.Imatinib concentration was measured in plasma,spleen,liver,kidney and brain using a HPLC assay.Non-compartmental pharmacokinetic approach was used to assess the disposition parameters.The plasma disposition profile was biphasic with a plateau-like second phase.The AUC0→∞ was 11.24 μg·h·mL-1,the elimination rate constant(kel) was 0.348 h-1 and the elimination half life(t1/2) was 2.0 h.The mean residence time(MRT) was 2.59 h,VSS was 1.44 L·kg-1 and clearance was 0.56 L·h·kg-1.Liver achieved the highest tissue exposure:CMAX = 18.72 μg·mL-1;AUC0→∞ = 58.18 μg·h·mL-1 and longest t1/2(4.29 h) and MRT(5.31 h).Kidney and spleen AUC0→∞ were 47.98 μg·h·mL-1 and 23.46 μg·h·mL-1,respectively.Half-life was 1.83 h for the kidney and 3.37 h for the spleen.Imatinib penetrated into the brain reaching ～1 μg·g-1.Upon correction by organ blood flow the spleen showed the largest uptake efficiency.Liposomal imatinib presented extensive biodistribution.The drug uptake kinetics showed mechanism differences amongst the tissues.These findings encourage the development of novel imatinib formulations to treat other cancers.展开更多
基金the International Medical University(IMU)for financial support:Grant#B0104RES(05)2007.
文摘Imatinib is an efficacious anticancer drug with a spectrum of potential antitumour applications limited by poor biodistribution at therapeutic concentrations to the tissues of interest.We assess the pharma-cokinetic and tissue distribution profile of imatinib in a liposome formulation.Its single dose(6.25 mg·kg-1) in a liposome formulation was administered iv to male mice.Imatinib concentration was measured in plasma,spleen,liver,kidney and brain using a HPLC assay.Non-compartmental pharmacokinetic approach was used to assess the disposition parameters.The plasma disposition profile was biphasic with a plateau-like second phase.The AUC0→∞ was 11.24 μg·h·mL-1,the elimination rate constant(kel) was 0.348 h-1 and the elimination half life(t1/2) was 2.0 h.The mean residence time(MRT) was 2.59 h,VSS was 1.44 L·kg-1 and clearance was 0.56 L·h·kg-1.Liver achieved the highest tissue exposure:CMAX = 18.72 μg·mL-1;AUC0→∞ = 58.18 μg·h·mL-1 and longest t1/2(4.29 h) and MRT(5.31 h).Kidney and spleen AUC0→∞ were 47.98 μg·h·mL-1 and 23.46 μg·h·mL-1,respectively.Half-life was 1.83 h for the kidney and 3.37 h for the spleen.Imatinib penetrated into the brain reaching ～1 μg·g-1.Upon correction by organ blood flow the spleen showed the largest uptake efficiency.Liposomal imatinib presented extensive biodistribution.The drug uptake kinetics showed mechanism differences amongst the tissues.These findings encourage the development of novel imatinib formulations to treat other cancers.
