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.

Neglected, Drug-Induced Platinum Accumulation Causes Immune Toxicity

“…Moreover, we found large individual and gender differences in platinum levels, perhaps related to polymorphisms of the GSTP1 and XRCC1 genes, and drug metabolic diversity in vivo (Sawers et al, 2014;Gu et al, 2015). Our finding is consistent with prior research showing that the elimination time for platinum is more than 25 times that for the intact platinum-based drug in the rat (Qin et al, 2019). In addition, there was an increasing trend over the first three time points, which reflected the platinum accumulation.…”

Characterization and Pharmacokinetic Evaluation of Oxaliplatin Long-Circulating Liposomes

“…As illustrated in Table 7 , the pharmacokinetic behavior of total platinum in plasma from free L-OHP, L-OHP bare lip, and L-OHP PEG lip compiled with the two-compartment model, characterized by a biphasic exponential decay with an initial rapid phase followed by a slower elimination terminal phase (Figures 6(b) – 6(d) ). The prolonged terminal elimination phase presumably represents inactive platinum complexes that were formed through chemical reactions with low molecular weight nucleophiles [ 20 ].…”

“…It was reported that after intravenous infusion, L-OHP is mainly identifiable in three compartments, plasma-bound platinum, ultrafiltrate plasma platinum, and erythrocyte-bound platinum [ 19 ]. The ultrafiltrate platinum contains the intact drug and the low molecular weight platinum metabolites, which are generally known to be the main active ingredients, whereas platinum bound to plasma proteins or erythrocytes is considered to be pharmacologically inactive [ 10 , 20 ]. Intact L-OHP was completely eliminated from blood circulation after 2 h of its intraperitoneal injection to rats [ 20 ].…”

“…The ultrafiltrate platinum contains the intact drug and the low molecular weight platinum metabolites, which are generally known to be the main active ingredients, whereas platinum bound to plasma proteins or erythrocytes is considered to be pharmacologically inactive [ 10 , 20 ]. Intact L-OHP was completely eliminated from blood circulation after 2 h of its intraperitoneal injection to rats [ 20 ]. Therefore, the quantification of only intact drug or only platinum metabolites projects a certain limitation on the real pharmacokinetic behavior of L-OHP in vivo .…”

PHF20 inhibition promotes apoptosis and cisplatin chemosensitivity via the OCT4‑p‑STAT3‑MCL1 signaling pathway in hypopharyngeal squamous cell carcinoma

“…Cisplatin is one of the most potent chemotherapeutic regimens that is widely used for the treatment of various types of solid tumor, including head and neck cancer, in clinical practice ( 36 , 37 ). However, its clinical efficiency is limited by chemoresistance and side effects, which includes mainly nephrotoxicity and bone marrow toxicity ( 29 , 38 ).…”