Oxol Mechanism of Action

Pharmacology: In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with 5-fluorouracil (5-FU), oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models [HT29 (colon), GR (mammary), and L1210 (leukemia)].
Mechanism of Action: Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter- and intra-strand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific.
Pharmacokinetics: The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. The decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t½; 0.43 hours and t½ 16.8 hours) and a long terminal elimination phase (t½; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour IV infusion of oxaliplatin injection at a dose of 85 mg/m² expressed as ultrafilterable platinum were Cmax of 0.814 μg/mL and volume of distribution of 440 L.
Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC_0-48hr) assessed over 3 cycles was moderate to low (23% and 6%, respectively). A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.
Distribution: At the end of a 2-hour infusion of OXOL, approximately 15% of the administered platinum is present in the systematic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m² every two weeks.
Metabolism: Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro.
Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species.
Elimination: The major route of platinum elimination is renal excretion. At five days after a single 2 hour infusion of OXOL, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. Platinum was cleared from plasma at a rate (10-17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal clearance of ultrafilterable platinum is significantly correlated with GFR.
The AUC_0-48hr of platinum in the plasma ultrafiltrate increases as renal function decreases. The AUC_0-48hr of platinum in patients with mild (creatinine clearance, CL_cr 50 to 80 mL/min), moderate (CL_cr 30 to <50 mL/min) and severe renal (CL_cr <30 mL/min) impairment is increased by about 60, 140 and 190%, respectively, compared to patients with normal renal function (CL_cr >80 mL/min).