Vadiei K, Siddik Z H, Khokhar A R, al-Baker S, Sampedro F, Perez-Soler R
Department of Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Cancer Chemother Pharmacol. 1992;30(5):365-9. doi: 10.1007/BF00689964.
The pharmacokinetics of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (L-NDDP) and cisplatin (CDDP) were studied after i.v. and i.p. administration of an equimolar dose (11 and 5 mg/kg for L-NDDP and CDDP, respectively) in the rat. The systemic absorption following i.p. administration was faster in rats receiving CDDP than in those receiving L-NDDP. Peak serum platinum (Pt) levels were observed at 30 min and 12 h after the i.p. administration of CDDP and L-NDDP, respectively. Administration by the i.v. route did not significantly alter the serum Pt levels for either compound. However, serum Pt levels were 2-3 times greater in animals treated with L-NDDP than in those treated with CDDP. The estimated pharmacokinetic parameters for each drug were independent of the route of administration, except for the clearance (Cl) of CDDP, which increased 2-fold following i.p. administration. In addition, significant differences in pharmacokinetic parameters were observed between drug-treatment groups that were independent of the route of administration: the serum Pt area under the concentration-time curve (AUC) was higher and the volume of distribution at steady state (Vdss) was lower in rats receiving L-NDDP. Pt levels measured at 6 h in the peritoneal fluid, peritoneal tissue, and intestine of rats receiving i.p. L-NDDP were higher than those observed in rats receiving either i.v. L-NDDP or CDDP by either route. Pt levels measured in the liver and spleen of rats receiving L-NDDP were independent of the route of administration and were significantly higher than those determined in rats treated with CDDP. In contrast, kidney Pt levels were lower in rats receiving L-NDDP than in rats receiving CDDP by either route. These results suggest that the prolongation of the mean retention time of L-NDDP in the peritoneum achieved after i.p. administration without compromising the systemic distribution of the drug may result in a significant enhancement of the therapeutic efficacy of L-NDDP against malignancies confined to the peritoneal cavity as compared with that of i.p. CDDP.
在大鼠静脉注射和腹腔注射等摩尔剂量（脂质体包裹的顺 - 双 - 新癸酸 - 反 - R，R - 1,2 - 二氨基环己烷铂（II）（L - NDDP）和顺铂（CDDP）分别为11和5 mg/kg）后，研究了它们的药代动力学。腹腔注射后，接受CDDP的大鼠全身吸收比接受L - NDDP的大鼠更快。腹腔注射CDDP和L - NDDP后，血清铂（Pt）峰值水平分别在30分钟和12小时观察到。静脉注射途径给药对两种化合物的血清Pt水平均无显著影响。然而，接受L - NDDP治疗的动物血清Pt水平比接受CDDP治疗的动物高2 - 3倍。每种药物的估计药代动力学参数与给药途径无关，但CDDP的清除率（Cl）在腹腔注射后增加了2倍。此外，在与给药途径无关的药物治疗组之间观察到药代动力学参数存在显著差异：接受L - NDDP的大鼠血清Pt浓度 - 时间曲线下面积（AUC）较高，稳态分布容积（Vdss）较低。腹腔注射L - NDDP的大鼠腹腔液、腹膜组织和肠道在6小时时测得的Pt水平高于通过任何一种途径接受静脉注射L - NDDP或CDDP的大鼠。接受L - NDDP的大鼠肝脏和脾脏中测得的Pt水平与给药途径无关，且显著高于接受CDDP治疗的大鼠。相反，接受L - NDDP的大鼠肾脏Pt水平低于通过任何一种途径接受CDDP的大鼠。这些结果表明，腹腔注射后L - NDDP在腹膜中的平均滞留时间延长，且不影响药物的全身分布，与腹腔注射CDDP相比，可能会显著提高L - NDDP对局限于腹腔的恶性肿瘤的治疗效果。
