Systemic Evaluation on the Pharmacokinetics of Platinum-Based Anticancer Drugs From Animal to Cell Level: Based on Total Platinum and Intact Drugs

Abstract

Cisplatin, carboplatin, and oxaliplatin are the common platinum-based anticancer drugs widely used in the chemotherapeutic treatment of solid tumors in clinic. However, the comprehensive pharmacokinetics of platinum-based anticancer drugs has not been fully understood yet. This leads to many limitations for the further studies on their pharmacology and toxicology. In this study, we conduct a systemic evaluation on the pharmacokinetics of three platinum analogues at animal and cell levels, with quantification of both total platinum and intact drugs. A detailed animal study to address and compare the different pharmacokinetic behaviors of three platinum analogues has been conducted in three biological matrices: blood, plasma, and ultrafiltrate plasma. Carboplatin showed an obviously different pharmacokinetic characteristic from cisplatin and oxaliplatin. On the one hand, carboplatin has the highest proportion of Pt distribution in ultrafiltrate plasma. On the other hand, carboplatin has the highest intact drug exposure and longest intact drug elimination time in blood, plasma, and ultrafiltrate plasma, which may explain its high hematotoxicity. Additionally, the cellular and subcellular pharmacokinetics of oxaliplatin in two colon cancer HCT-116/LOVO cell lines has been elucidated for the first time. The biotransformation of intact oxaliplatin in cells was rapid with a fast elimination, however, the generated platinum-containing metabolites still exist within cells. The distribution of total platinum in the cytosol is higher than in the mitochondria, followed by the nucleus. Enrichment of platinum in mitochondria may affect the respiratory chain or energy metabolism, and further lead to cell apoptosis, which may indicate mitochondria as another potential target for efficacy and toxicity of oxaliplatin.

Keywords: carboplatin; cisplatin; oxaliplatin; pharmacokinetics; total platinum.

Figure 1

Chemical structures of cisplatin, carboplatin and oxaliplatin.

Figure 2

Intact drug and total platinum concentration-time profiles in blood (A and B), plasma (C and D), and ultrafiltrate plasma (E and F) after intraperitoneal injection of equal moles of three platinum-based drugs to rats (equivalent to platinum at 16.7 nmol/kg). All data are presented as mean ± sd (n = 6).

Figure 3

Cellular total platinum (A) and intact oxaliplatin (B) over time with 200 μm oxaliplatin exposure to HCT-116 and LOVO cell lines. Uptake of total platinum (C) and intact oxaliplatin (D) in HCT-116 and LOVO cell lines at different medium concentrations of oxaliplatin (20–500 μM) for 30 min incubation. The cellular total platinum (E) and oxaliplatin (F) uptake as a function of treatment temperature with 200 μm oxaliplatin exposure to HCT-116 and LOVO cell lines for 30 min. All data are presented as mean ± sd (n = 3). The uptake difference between two groups at 4^◦C and 37^◦C was highly significant (***P < 0.001).

Figure 4

The time course of total platinum (A) and oxaliplatin (B) in HCT-116 and LOVO cell lines after incubation with 200 μm drug-containing medium for 30 min and then replaced by fresh medium without drug. All data are presented as mean ± sd (n = 3).

Figure 5

The concentration of Pt in different subcellular organelles of HCT-116 cells (A)/LOVO cells (B) at different incubation time treated with 200 μm drug-containing medium. All data were expressed as (ng Pt/mg protein of subcellular organelles) and presented as mean ± sd (n = 3).