Chemical formula: C₉H₁₁F₂N₃O₄ Molecular mass: 263.198 g/mol PubChem compound: 60750
Gemcitabine (dFdC), which is a pyrimidine antimetabolite, is metabolised intracellularly by nucleoside kinase to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is due to inhibition of DNA synthesis by two mechanisms of action by dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase, which is uniquely responsible for catalysing the reactions that produce deoxynucleoside triphosphates (dCTP) for DNA synthesis. Inhibition of this enzyme by dFdCDP reduces the concentration of deoxynucleosides in general and, in particular, dCTP. Second, dFdCTP competes with dCTP for incorporation into DNA (self-potentiation).
Likewise, a small amount of gemcitabine may also be incorporated into RNA. Thus, the reduced intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. DNA polymerase epsilon lacks the ability to eliminate gemcitabine and to repair the growing DNA strands. After gemcitabine is incorporated into DNA, one 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 appears to induce the programmed cell death process known as apoptosis.
Gemcitabine shows significant cytotoxic effects against a variety of cultured murine and human tumour cells. Its action is phase-specific such that gemcitabine primarily kills cells that are undergoing DNA synthesis (S-phase) and, under certain circumstances, blocks the progression of cells at the junction of the G1/S phase boundary. In vitro, the cytotoxic effect of gemcitabine is dependent on both concentration and time.
In animal tumour models, antitumoural activity of gemcitabine is schedule-dependent. When gemcitabine is administered daily, high mortality among the animals but minimal antitumoural activity is observed. If, however, gemcitabine is given every third or fourth day, it can be administered in nonlethal doses with substantial antitumoural activity against a broad spectrum of mouse tumours.
The pharmacokinetics of gemcitabine have been examined in 353 patients in seven studies. The 121women and 232 men ranged in age from 29 to 79 years. Of these patients, approximately 45% had non-small cell lung cancer and 35% were diagnosed with pancreatic cancer. The following pharmacokinetic parameters were obtained for doses ranging from 500 to 2,592 mg/m² that were infused from 0.4 to 1.2 hours.
Peak plasma concentrations (obtained within 5 minutes of the end of the infusion) were 3.2 to 45.5 μg/ml. Plasma concentrations of the parent compound following a dose of 1,000 mg/m²/30-minutes are greater than 5 μg/ml for approximately 30-minutes after the end of the infusion, and greater than 0.4 μg/ml for an additional hour.
The volume of distribution of the central compartment was 12.4 l/m² for women and 17.5 l/m² for men (inter-individual variability was 91.9%). The volume of distribution of the peripheral compartment was 47.4 l/m². The volume of the peripheral compartment was not sensitive to gender. The plasma protein binding was considered to be negligible.
This ranged from 42 to 94 minutes depending on age and gender. For the recommended dosing schedule, gemcitabine elimination should be virtually complete within 5 to 11 hours of the start of the infusion. Gemcitabine does not accumulate when administered once weekly.
Gemcitabine is rapidly metabolised by cytidine deaminase in the liver, kidney, blood and other tissues. Intracellular metabolism of gemcitabine produces the gemcitabine mono, di and triphosphates (dFdCMP, dFdCDP and dFdCTP) of which dFdCDP and dFdCTP are considered active. These intracellular metabolites have not been detected in plasma or urine. The primary metabolite, 2'-deoxy-2', 2'-difluorouridine (dFdU), is not active and is found in plasma and urine.
Systemic clearance ranged from 29.2 l/hr/m² to 92.2 l/hr/m² depending on gender and age (inter-individual variability was 52.2%). Clearance for women is approximately 25% lower than the values for men. Although rapid, clearance for both men and women appears to decrease with age. For the recommended gemcitabine dose of 1000 mg/m² given as a 30-minute infusion, lower clearance values for women and men should not necessitate a decrease in the gemcitabine dose. Urinary excretion: Less than 10% is excreted as unchanged drug.
Renal clearance was 2 to 7 l/hr/m².
During the week following administration, 92 to 98% of the dose of gemcitabine administered is recovered, 99% in the urine, mainly in the form of dFdU and 1% of the dose is excreted in faeces.
This metabolite can be found in peripheral blood mononuclear cells and the information below refers to these cells. Intracellular concentrations increase in proportion to gemcitabine doses of 35-350 mg/m²/30-minutes, which give steady state concentrations of 0.4-5 μg/ml. At gemcitabine plasma concentrations above 5 μg/ml, dFdCTP levels do not increase, suggesting that the formation is saturable in these cells.
Half-life of terminal elimination: 0.7-12 hours.
Peak plasma concentrations (3-15 minutes after end of 30-minute infusion, 1000 mg/m²): 28-52 μg/ml. Trough concentration following once weekly dosing: 0.07-1.12 μg/ml, with no apparent accumulation. Triphasic plasma concentration versus time curve, mean half-life of terminal phase 65 hours (range 33-84 hr).
Formation of dFdU from parent compound: 91%-98%.
Mean volume of distribution of central compartment: 18 l/m² (range 11-22 l/m²).
Mean steady state volume of distribution (Vss): 150 l/m² (range 96-228 l/m²).
Tissue distribution:* Extensive.
Mean apparent clearance: 2.5 l/hr/m² (range 1-4 l/hr/m²).
Urinary excretion: All.
Combination therapy did not alter the pharmacokinetics of either gemcitabine or paclitaxel.
When given in combination with carboplatin the pharmacokinetics of gemcitabine were not altered.
Mild to moderate renal insufficiency (GFR from 30 ml/min to 80 ml/min) has no consistent, significant effect on gemcitabine pharmacokinetics.
In repeat-dose studies of up to 6 months in duration in mice and dogs, the principal finding was schedule and dose-dependent haematopoietic suppression which was reversible.
Gemcitabine is mutagenic in an in vitro mutation test and an in vivo bone marrow micronucleus test. Long term animal studies evaluating the carcinogenic potential have not been performed.
In fertility studies, gemcitabine caused reversible hypospermatogenesis in male mice. No effect on the fertility of females has been detected.
Evaluation of experimental animal studies has shown reproductive toxicity e.g. birth defects and other effects on the development of the embryo or foetus, the course of gestation or peri- and postnatal development.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
