Boughattas N A, Hecquet B, Fournier C, Bruguerolle B, Trabelsi H, Bouzouita K, Omrane B, Lévi F
Départment de Pharmacologie, Faculté de Médecine, Monastir, Tunisia.
Biopharm Drug Dispos. 1994 Dec;15(9):761-73. doi: 10.1002/bdd.2510150904.
Carboplatin (CBDCA) and oxaliplatin (I-OHP) are non-nephrotoxic platinum (Pt) compounds, which exert their main respective toxicities on the bone marrow and on the intestinal mucosa in mice. Plasma and red blood cell (RBC) drug dispositions were investigated in 324 male B6D2F1 mice after a single IV injection of CBDCA (72 mg kg-1) or I-OHP (17 mg kg-1). Since the toxicities of either drug largely depended upon circadian dosing time, such a pharmacokinetic study was performed following injection of either Pt complex at a time of low (16 h after light onset-HALO), intermediate (0 HALO) or high (8 HALO) toxicity. Pt concentrations in plasma ultrafiltrate (PUF) and in total plasma declined in parallel and became barely detectable by 2 h following CBDCA injection. Conversely, free Pt became undetectable 1 h after I-OHP injection, whereas sustained levels of total Pt were found 24 h post dosing. This suggested that I-OHP had a high binding affinity for plasma proteins. Mean values of t1/2 alpha and mean residence time (MRT) of free Pt for I-OHP (6.7 min and 9.7 min respectively) were half those of CBDCA (12.5 min and 18.1 min respectively). The two drugs had a similar initial volume of distribution (Vdi) of free Pt (10.5 mL) in mice. However, plasma clearance of I-OHP was twice as high (1.06 mL min-1) as that of CBDCA (0.58 mL min-1). Free Pt AUCs were eight to ten times lower for I-OHP than for CBDCA. In contrast, erythrocyte Pt AUCs were three to four times as high for I-OHP as for CBDCA. Circadian changes in pharmacokinetic parameters were large, yet limited to the initial distribution phase (C0, t1/2 alpha, Vdi) as well as mean residence time. The smallest Vdi and the fastest plasma elimination occurred when either drug was injected at 0 HALO. The largest Vdi and the longest elimination were however observed at 8 HALO for CBDCA and 16 HALO for I-OHP. No consistent relationship was found for both Pt complexes with regard to circadian changes in blood pharmacokinetics and in target organ toxicities. The major pharmacokinetics differences between CBDCA and I-OHP were related to both protein binding and RBC handling.
卡铂（CBDCA）和奥沙利铂（I-OHP）是无肾毒性的铂（Pt）化合物，它们在小鼠体内主要分别对骨髓和肠黏膜产生毒性。在324只雄性B6D2F1小鼠单次静脉注射CBDCA（72毫克/千克）或I-OHP（17毫克/千克）后，研究了血浆和红细胞（RBC）中的药物处置情况。由于这两种药物的毒性在很大程度上取决于昼夜给药时间，因此在低毒性（光照开始后16小时 - HALO）、中等毒性（0 HALO）或高毒性（8 HALO）时间注射铂络合物后进行了这样的药代动力学研究。CBDCA注射后2小时，血浆超滤液（PUF）和总血浆中的Pt浓度平行下降，几乎检测不到。相反，I-OHP注射后1小时游离Pt就检测不到了，而给药后24小时总Pt水平持续存在。这表明I-OHP对血浆蛋白具有高结合亲和力。I-OHP游离Pt的t1/2α平均值和平均驻留时间（MRT）（分别为6.7分钟和9.7分钟）是CBDCA（分别为12.5分钟和18.1分钟）的一半。两种药物在小鼠体内游离Pt的初始分布容积（Vdi）相似（10.5毫升）。然而，I-OHP的血浆清除率（1.06毫升/分钟）是CBDCA（0.58毫升/分钟）的两倍。I-OHP的游离Pt曲线下面积（AUC）比CBDCA低八到十倍。相比之下，I-OHP的红细胞Pt AUC是CBDCA的三到四倍。药代动力学参数的昼夜变化很大，但仅限于初始分布阶段（C0、t1/2α、Vdi）以及平均驻留时间。当在0 HALO注射任何一种药物时，Vdi最小，血浆消除最快。然而，对于CBDCA在8 HALO和I-OHP在16 HALO时观察到最大的Vdi和最长的消除时间。对于这两种铂络合物，在血液药代动力学和靶器官毒性的昼夜变化方面未发现一致的关系。CBDCA和I-OHP之间主要的药代动力学差异与蛋白结合和红细胞处理有关。
