Indication |
For the first-line treatment of patients with metastatic breast cancer, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer and as first-line treatment for patients with adenocarcinoma of the pancreas. |
Pharmacodynamics |
Gemcitabine is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (or DNA synthesis phase of the cell cycle), stopping normal development and division. Gemcitabine blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because Gemcitabine blocks the incorporation of the thymidine nucleotide into the DNA strand. |
Mechanism of action |
Gemcitabine inhibits thymidylate synthetase, leading to inhibition of DNA synthesis and cell death. Gemcitabine is a prodrug so activity occurs as a result of intracellular conversion to two active metabolites, gemcitabine diphosphate and gemcitabine triphosphate by deoxycitidine kinase. Gemcitabine diphosphate also inhibits ribonucleotide reductase, the enzyme responsible for catalyzing synthesis of deoxynucleoside triphosphates required for DNA synthesis. Finally, Gemcitabine triphosphate (diflurorodeoxycytidine triphosphate) competes with endogenous deoxynucleoside triphosphates for incorporation into DNA. |
Absorption |
100% |
Volume of distribution |
- 50 L/m^2 [infusions lasting <70 minutes]
- 370 L/m^2 [long infusions]
|
Protein binding |
Plasma protein binding is negligible (<10%) |
Metabolism |
Transformed via nucleoside kinases to two active metabolites, gemcitabine diphosphate and gemcitabine triphosphate. Can also undergo deamination via cytidine deaminase to an inactive uracil metabolite (dFdU).
|
Route of elimination |
Not Available |
Half life |
Short infusions ranged from 32 to 94 minutes, and the value for long infusions vary from 245 to 638 minutes, depending on age and gender. |
Clearance |
- 92.2 L/hr/m2 [Men 29 yrs]
- 75.7 L/hr/m2 [Men 45 yrs]
- 55.1 L/hr/m2 [Men 65 yrs]
- 40.7 L/hr/m2 [Men 79 yrs]
- 69.4 L/hr/m2 [Women 29 yrs]
- 57 L/hr/m2 [Women 45 yrs]
- 41.5 L/hr/m2 [Women 65 yrs]
- 30.7 L/hr/m2 [Women 79 yrs]
|
Toxicity |
Myelosuppression, paresthesias, and severe rash were the principal toxicities, LD50=500 mg/kg (orally in mice and rats) |
Affected organisms |
|
Pathways |
Pathway |
Name |
SMPDB ID |
|
Gemcitabine Pathway |
SMP00446 |
|