Newman R A, Fuentes A, Covey J M, Benvenuto J A
Department of Clinical Investigation, University of Texas, M. D. Anderson Cancer Center, Houston 77030.
Drug Metab Dispos. 1994 May-Jun;22(3):428-32.
The preclinical pharmacology and pharmacokinetics of the natural marine product dolastatin 10 were investigated. Pharmacokinetics of [3H]dolastatin 10 were determined in CD2F1 mice after intravenous, subcutaneous, and intraperitoneal routes of administration. After intravenous injection (0.24 mg/kg), plasma drug concentration declined rapidly and was cleared from plasma with a half-life of 5.6 hr. After a subcutaneous dose of 0.32 mg/kg, dolastatin 10 concentrations slowly rose to a maximum of 11 ng/ml and then declined with an elimination half-life of 3.7 hr. Most of the radioactivity in plasma was found to be from drug-derived radiolabeled products and not from parent compound. Urinary excretion of dolastatin 10 was < 2% of the administered dose, irrespective of the route of administration. In vitro, dolastatin 10 was stable in mouse plasma for at least 24 hr at 37 degrees C. The drug was also highly protein-bound (> 81%) in human, dog, and mouse plasmas. Dolastatin 10 underwent rapid conversion to more polar products after incubation with whole liver homogenate or the S9 fraction from rate liver. One of these metabolites was identified by mass spectrometry as a dihydroxy derivative of dolastatin 10.
对天然海洋产物多拉司他汀10的临床前药理学和药代动力学进行了研究。在CD2F1小鼠中，通过静脉内、皮下和腹腔内给药途径测定了[3H]多拉司他汀10的药代动力学。静脉注射（0.24mg/kg）后，血浆药物浓度迅速下降，血浆清除半衰期为5.6小时。皮下注射0.32mg/kg剂量后，多拉司他汀10的浓度缓慢上升至最高11ng/ml，然后下降，消除半衰期为3.7小时。发现血浆中的大部分放射性来自药物衍生的放射性标记产物，而非母体化合物。无论给药途径如何，多拉司他汀10的尿排泄量均小于给药剂量的2%。在体外，多拉司他汀10在37℃的小鼠血浆中至少稳定24小时。该药物在人、狗和小鼠血浆中也具有高度的蛋白结合率（>81%）。多拉司他汀10与全肝匀浆或大鼠肝脏的S9组分孵育后迅速转化为极性更强的产物。其中一种代谢产物通过质谱鉴定为多拉司他汀10的二羟基衍生物。
