Gemita RTU Mechanism of Action

PHARMACOLOGY: Mechanism of action: Gemcitabine, a pyrimidine analog, has a wide spectrum of antitumor activity. It is cell-cycle phase specific and kills the cells undergoing DNA synthesis in the S-phase. It also blocks the progression of cells through the G1/S-phases. Gemcitabine is metabolized intracellularly to two active metabolites, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). The diphosphate of gemcitabine appears to be an effective inhibitor of ribonucleotide reductase and this may be irreversible. Ribonucleotide reductase inhibition results in depletion of cellular deoxyribo-nucleotide triphosphate pools. The effect of cellular depletion of deoxycytidine triphosphate is a self-potentiation of the cytotoxicity of gemcitabine as gemcitabine triphosphate (dFdCTP) competes with deoxycytidine triphosphate for incorporation into DNA. Gemcitabine needs to be activated by deoxycytidine kinase and other kinases to its triphosphate, gemcitabine triphosphate, which can be incorporated into RNA and DNA. The latter effect is considered to be responsible for its antitumor effect and causes masked chain termination and inhibition of DNA repair. This effect may be of importance for combination with DNA interacting agents.
Pharmacokinetics: Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. In a radiolabeled study on gemcitabine in five patients who received a single 1000 mg/m²/30 minute infusion of drug, ninety two to ninety eight percent of the dose was recovered, almost entirely in the urine within one week's time. The inactive uracil metabolite, 2'-deoxy-2', 2'-difluorouridine (dFdU) and gemcitabine accounted for 99% of the excreted dose. The plasma protein binding is negligible for gemcitabine. Pharmacokinetic study of gemcitabine was carried out in 353 patients, with various solid tumors. The total gemcitabine dose varied from 500 to 3600 mg/m². Using the data from patients treated for varying durations of therapy given weekly with periodic rest weeks and using both short infusions (<70 minutes) and long infusions (70 to 285 minutes) the pharmaco-kinetic parameters were derived. Combined single and multiple dose studies showed that duration of infusion, age and gender significantly influenced the volume of distribution and drug clearance of gemcitabine. Base on patient characteristics or the duration of infusion the differences in either clearance or volume of distribution result in changes in half-life and plasma concentrations. The effects of significant renal or hepatic insufficiency on the disposition of gemcitabine have not been assessed. In mononuclear cells, the half-life of the terminal phase for gemcitabine triphosphate ranges from 1.7 to 19.4 hours. The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells.