Kemoplat Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: KEMOPLAT 1 mg/ml is an antineoplastic agent with biochemical properties similar to those of bifunctional alkylating agents. Cisplatin enter cells by diffusion and binds covalently to DNA bases and disrupts DNA function. Hydrolysis of chloride in its structure is responsible for formation of activated species of the drug, which reacts with nucleic acids and protein. KEMOPLAT exerts its action by forming both intrastrand and interstrand cross-links of complementary strands of DNA, thus inhibiting DNA synthesis. Protein and RNA synthesis are also inhibited to a lesser extent. Its antineoplastic actions are not cell-cycle specific.
Pharmacokinetics: Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with a half-life of about 20 to 30 minutes following bolus administrations of 50 or 100 mg/m² doses. Monoexponential decay and plasma half-lives of about 0.5 hour are also seen following two hour or seven hour infusions of 100 mg/m². After the latter, the total-body clearances and volumes of distribution at steady state for cisplatin are about 15 to 16 L/h/m² and 11 to 12 L/m². Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to enzyme-catalyzed metabolism. Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is characteristic of normal drug-protein binding. However, the platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins including albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five days or more. Over a dose range of 40 to 140 mg cisplatin/m² given as a bolus injection or as infusions varying in length from 1 hour to 24 hours, from 10% to about 40% of the administered platinum is excreted in the urine in 24 hours. Over five days following administration of 40 to 100 mg/m² doses given as rapid, 2 to 3 hour, or 6 to 8 hour infusions, a mean of 35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary recoveries of platinum of about 14% to 30% of the dose are found following five daily administrations of 20, 30, or 40 mg/m²/day.
The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose excreted within one hour after administration of 50 mg/m². The mean renal clearance of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m² following administration of 100 mg/m² as 2 hour or 6 to 7 hour infusions, respectively. The renal clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and individual variability in the extent of active secretion and possible tubular reabsorption. There is a potential for accumulation of ultra filterable platinum plasma concentrations whenever cisplatin is administered on a daily basis but not when dosed on an intermittent basis.