Pharmacokinetics and biotransformations of oxaliplatin in comparison with ormaplatin following a single bolus intravenous injection in rats

Purpose: Traditionally ultrafilterable Pt has been used to estimate the body exposure to platinum drugs. However, previous studies have shown that ultrafilterable Pt consists of both cytotoxic and inert biotransformation products of platinum drugs. Therefore, it has been proposed that pharmacokinetic parameters of the parent drug and its cytotoxic biotransformation products are more likely to be correlated with the drug toxicity and efficacy than those of ultrafilterable Pt. Oxaliplatin and ormaplatin are likely to form very similar biotransformation products in vivo based on previous studies. However, ormaplatin causes severe and irreversible neurotoxicity while oxaliplatin causes moderate and reversible neurotoxicity. To evaluate the hypothesis that the neurotoxicity is associated with the pharmacokinetics of active biotransformation products, we investigated the biotransformations and pharmacokinetics of oxaliplatin and ormaplatin in rats at equimolar doses. Methods: 3H-oxaliplatin and H-3-ormaplatin were administered to Wistar male rats through single bolus i.v. injections (20 mu mol/kg). Blood was sampled from 3.5 min to 360 min and centrifuged at 2000 g to separate the plasma from red blood cells (RBCs). The RBCs were sonicated and centrifuged at 13 000g to separate the cytosol from the membrane fraction. Both plasma and RBC cytosol were filtered through YMT30 membranes (M-r = 30 000 kDa), and the ultrafiltrates were analyzed using a single column HPLC technique to identify and quantitate the biotransformation products. The pharmacokinetics of oxaliplatin, ormaplatin, and their biotransformation products were characterized utilizing the curve stripping and nonlinear least-squares fitting program RSTRIP. Results: The decays of total, plasma, plasma ultrafilterable (PUFS, RBC-bound, and plasma protein-bound Pt-dach (only Pt species with an intact dach carrier ligand were quantitated in this study) were described by biphasic curves. No significant kinetic differences between oxaliplatin and ormaplatin were observed for total, plasma, and PUF Pt-dach in the initial a decay phase. However, Pt-dach bound to plasma proteins fourfold more quickly for ormaplatin than for oxaliplatin, and the AUC for Pt-dach bound to plasma proteins was twofold higher for ormaplatin than for oxaliplatin. The concentration of RBC-bound Pt-dach was highest at the initial time-point of 3.5 min for both drugs, which suggested a very rapid RBC uptake. The binding of Pt-dach to RBCs was slightly greater initially for ormaplatin than for oxaliplatin. However, the RBC-bound Pt-dach decayed more rapidly for ormaplatin (t(1/2 alpha RBC) = 5.1 min) than for oxaliplatin (t(1/2 alpha RBC) = 15.3 min). Thus the AUC(RBC) was slightly greater for oxaliplatin than for ormaplatin. The AUC was also slightly greater for oxaliplatin than for ormaplatin for the Pt-dach associated with the RBC membrane and RBC cytosolic proteins. However, there was no significant difference between oxaliplatin and ormaplatin for Pt-dach in the RBC cytosolic ultrafiltrate. There was also no significant difference in the AUC(PUf) between oxaliplatin and ormaplatin. Both oxaliplatin and ormaplatin produced the same types of major plasma biotransformation products including Pt(dach)Cl-2, Pt(dach)(Cys)(2), Pt(dach)(GSH)(2), Pt(dach)(GSH), Pt(dach)(Met), and free dach. The decays of oxaliplatin, ormaplatin, and their biotransformation products were described by biphasic curves. The C-max and AUC were 19- and 15-fold higher, respectively, for oxaliplatin than for ormaplatin. However, the C-max and AUC were 29- and 16-fold less for Pt(dach)Cl-2, derived from oxaliplatin than for that derived from ormaplatin. No significant differences were observed among the C-max values and AUC values for the other plasma biotransformation products. Pt-dach species formed in RBCs were also identified and quantitated. Oxaliplatin was observed in the RBC cytosol, while no ormaplatin was found. The same types of major RBC biotransformation products were observed including Pt(dach)Cl-2, Pt(dach)(Cys)(2), Pt(dach)(GSW), Pt(dach) (GSH)?, and free dach. Among these Pt-dach species, Pt(dach)Cl-2 was present at a twofold lower concentration initially but persisted longer for oxaliplatin than for ormaplatin. while the other RBC biotransformation products behaved kinetically similarly and no significant AUC differences were observed. Conclusion: Our study suggests that the different toxicity and efficacy profiles between oxaliplatin and ormaplatin may be related to the different pharmacokinetic features of these two drugs, especially the different plasma concentrations of their common biotransformation product Pt(dach)Cl-2. This in turn suggests that Pt(dach)Cl-2 and its hydrolysis products may be uniquely neurotoxic.