Gemtabin Mechanism of Action

Pharmacology: Pharmacodynamics: Cytotoxic Activity in Cell Culture Models: Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells through the G1/S-phase boundary.
Cellular Metabolism and Mechanism of Action: Gemcitabine (dFdC) is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides.
The cytotoxic action of gemcitabine appears to be due to inhibition of DNA synthesis by 2 actions of dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase which is uniquely responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by dFdCDP causes a reduction in the concentrations of deoxynucleosides in general and especially in that of dCTP. Secondly, dFdCTP competes with dCTP for incorporation into DNA (self-potentiation). Thus, the reduction in the intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. Deoxyribonucleic acid polymerase epsilon is essentially unable to remove gemcitabine and repair the growing DNA strands. After gemcitabine is incorporated into DNA, 1 additional nucleotide is added to the growing DNA strands. After this addition, there is essentially a complete inhibition in further DNA synthesis (masked chain termination). After incorporation into DNA, gemcitabine then appears to induce the programmed cellular death process known as apoptosis.
Pharmacokinetics: Gemcitabine is rapidly cleared from plasma, principally by metabolism to the inactive metabolite, 2'-deoxy-2',2'-diflurouradine (dFdU). Less than 10% of an IV dose is recovered in urine as unchanged gemcitabine.
Gemcitabine and dFdU are the only compounds found in plasma and comprise 99% of the drug-related material recovered in urine. Gemcitabine plasma protein-binding is negligible. Population pharmacokinetic analyses of single- and multiple-dose studies show that the volume of distribution is significantly influenced by gender.
Systemic clearance is affected by age and gender. These effects result in differences in plasma gemcitabine concentration and in rate of elimination (t_1/2) from the systemic circulation. Systemic clearance ranged from approximately 30 L/hr/m² to approximately 90 L/hr/m². With recommended infusion time, t_1/2 ranged from 32-94 min, depending on age and gender.