Darvari Ramin, Boroujerdi Mehdi
Epic Therapeutics Inc., a Subsidiary of Baxter Healthcare Corporation, Norwood, MA 02062, USA.
Cancer Chemother Pharmacol. 2005 Nov;56(5):497-509. doi: 10.1007/s00280-005-1001-8. Epub 2005 Jun 4.
The in vivo effect of modulators of P-glycoprotein (Pgp) on organ accumulation of substrates of Pgp has not been fully investigated. We investigated the influence of a Pgp modulator (tamoxifen, TAM) on the pharmacokinetics and toxicodynamics of a Pgp substrate (doxorubicin, DOX) in rats.
TAM was administered daily for 11 days before the administration of DOX in male Sprague-Dawley rats, with all doses being clinically relevant. The experimental design of the project consisted of two different protocols. One was to investigate the effect of DOX on the time course of Pgp-ATPase activity, sarcoplasmic reticulum Ca(2+) -ATPase (SERCA) activity, and DOX concentration in the heart, liver, and kidneys of TAM-pretreated animals; the other protocol was to study the effect of TAM pretreatment on the disposition of DOX in the body by investigating its time course in plasma, urine and bile.
The simultaneous curve fitting of plasma data with urine and bile data with the help of the related pharmacokinetic equations provided the calculated parameters and constants. The first-order rate constants between the central and the myocardial compartments (k(1H) and k(H1)) were decreased in the TAM-treated group. The treatment also significantly reduced the k(1H)/k(H1) ratio in comparison to that of the control group. The first-order biliary elimination rate constant (k(b)) was significantly decreased (29%) in the TAM-treated group. The reduction was estimated in comparison with that of the control group. This reduction could be attributed to the inhibitory effect of TAM on Pgp located on biliary canicular membranes. The initial reduction of Pgp activity in TAM-treated group was at 60% of the basal level. The activity declined and reached a plateau at 20% of the basal activity after 6 h and remained at that level for 24 h. The area under the curves of Pgp-ATPase activity time (AUC(Activity 0-24)) following DOX administration in TAM-treated group was significantly lower than that of the control group, indicating an overall inhibitory effect of TAM on Pgp-ATPase activity under the protocol of this study. The area under the curves of the SERCA activity-time curve following DOX administration in TAM-treated group demonstrated a 15% reduction in AUC(Activity 0-24) in comparison with that of the control group, an indication of increased toxicity. The amount of myocardial Pgp in the 24-h period following DOX administration was comparable to the control group and showed no significant deviation from the basal levels of the protein.
The effect of TAM on DOX accumulation in the myocardial tissue and the increase in cardiotoxicity can be related to the net inhibitory effect of TAM on the efflux activity of Pgp in the heart. The results of the present study supported the hypothesis of the project that multiple regimen pretreatment with Pgp modulator TAM increases the DOX accumulation in the heart and promotes DOX-induced cardiotoxicity.
P-糖蛋白（Pgp）调节剂对Pgp底物在器官中的蓄积的体内效应尚未得到充分研究。我们研究了一种Pgp调节剂（他莫昔芬，TAM）对大鼠体内Pgp底物（阿霉素，DOX）的药代动力学和毒代动力学的影响。
在雄性Sprague-Dawley大鼠中，于给予DOX前每日给予TAM，持续11天，所有剂量均与临床相关。该项目的实验设计包括两种不同的方案。一种是研究DOX对TAM预处理动物心脏、肝脏和肾脏中Pgp-ATP酶活性、肌浆网Ca(2+) -ATP酶（SERCA）活性以及DOX浓度随时间变化的影响；另一种方案是通过研究DOX在血浆、尿液和胆汁中的时间进程，来研究TAM预处理对DOX在体内处置的影响。
借助相关药代动力学方程对血浆数据与尿液和胆汁数据进行同步曲线拟合，得出计算参数和常数。TAM治疗组中心室与心肌隔室之间的一级速率常数（k(1H)和k(H1)）降低。与对照组相比，该治疗还显著降低了k(1H)/k(H1)比值。TAM治疗组的一级胆汁消除速率常数（k(b)）显著降低（29%）。该降低是与对照组相比估算得出的。这种降低可归因于TAM对胆小管膜上Pgp的抑制作用。TAM治疗组中Pgp活性最初降低至基础水平的60%。6小时后活性下降并达到基础活性的20%的平台期，并在该水平维持24小时。TAM治疗组在给予DOX后Pgp-ATP酶活性时间曲线下面积（AUC(活性0 - 24)）显著低于对照组，表明在本研究方案下TAM对Pgp-ATP酶活性具有总体抑制作用。TAM治疗组在给予DOX后SERCA活性 - 时间曲线下面积与对照组相比，AUC(活性0 - 24)降低了15%，表明毒性增加。给予DOX后24小时内心肌中Pgp的量与对照组相当，且与该蛋白的基础水平无显著偏差。
TAM对心肌组织中DOX蓄积的影响以及心脏毒性的增加可能与TAM对心脏中Pgp外排活性的净抑制作用有关。本研究结果支持了该项目的假设，即Pgp调节剂TAM的多方案预处理会增加心脏中DOX的蓄积并促进DOX诱导的心脏毒性。
