Browsing by Subject "Gemcitabine"
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Item Pharmacometric modeling of anti-cancer agents: application to gemcitabine, PQIP and irinotecan.(2010-07) Khatri, AmitWe performed pharmacometric modeling of irinotecan, PQIP and gemcitabine. Irinotecan is a DNA topoisomerase-I inhibitor used in colorectal and brain tumors. One of our aims was to show that that cranial radiation, delivered during irinotecan administration, can enhance uptake in to cerebral-spinal fluid (CSF), and also to characterize the pharmacokinetics of irinotecan and its metabolites SN38 and APC in plasma and CSF in rats. The concentration-time data in plasma and CSF were analyzed by nonlinear mixed-effects modeling using FOCE-I method in NONMEM. The analysis showed that cranial radiation delivered during irinotecan administration enhances uptake in to CSF. The second aim of dissertation was to quantitatively evaluate the drug administration sequence effects of insulin-like growth factor type-1 receptor inhibitors (IGF-1R) with gemcitabine in vitro . Gemcitabine is a nucleoside analogue approved for a variety of solid tumors, while PQIP is an investigational IGF-1R inhibitor. In vitro experiments were conducted in 24-well tissue culture plates using MCF-7, MDA-MB-231 and Hs-578T human breast cancer cell lines. Viable cells were counted every day following the day of drug exposure. The effect of sequence on cell-kill was analyzed by bayesian techniques using WinBUGS. We found that exposure with gemcitabine first, followed by PQIP (GP sequence) was either superior or equivalent to the reverse sequence (PG sequence) with these drugs. The third aim of dissertation was to perform a population pharmacokinetic analysis of gemcitabine and its metabolites dFdU and dFdCTP in patients with solid tumors and to determine patient specific covariates associated with their disposition. Concentration data were obtained in 40 patients with solid tumors. The concentration-time data were analyzed by nonlinear mixed-effects modeling using first-order conditional estimation method with interaction (FOCE-I) in NONMEM. We found that Body surface area (BSA) and age were significant covariates for the disposition of gemcitabine, while creatinine clearance (CL CR ) and BSA were found to be significant covariates for the disposition of dFdU. We also found that patients who received gemcitabine at a rate less that 25 mg/m 2 /min had higher formation of dFdCTP than those who received gemcitabine at a rate greater than 25 mg/m 2 /min.Item Role of equilibrative nucleoside transporters 1 and 2 in the transport and disposition of gemcitabine and its metabolites in cervical carcinoma.(2010-08) Hodge, Lucy SahrGemcitabine is a nucleoside analog used as a radiosensitizer for the treatment of locally advanced cervical carcinoma. Yet, despite its efficacy when administered concomitantly with radiation, gemcitabine therapy is not without side effects. The utility of delivering gemcitabine directly to the cervix was explored through the use of a novel drug delivery device, CerviPrep(TM). Local administration to the cervix led to clinically relevant concentrations of gemcitabine in cervical tissue and plasma, while no gemcitabine was detected in the systemic circulation and no side effects were reported. Our data suggest that targeting gemcitabine delivery to the cervix can limit systemic exposure and toxicity while achieving cytotoxic concentrations of drug at the target site. Despite its widespread use in cervical carcinoma, little is known about the disposition of gemcitabine in this tissue. As a nucleoside analog, gemcitabine is a substrate for the equilibrative nucleoside transporters (hENT), and patient response to gemcitabine therapy has been associated with the expression of these proteins. A characterization of hENT1 and hENT2 in both malignant and normal cervical tissue was undertaken, and while no effect of malignancy was observed on hENT1 protein expression, hENT2 protein was nearly three-fold higher in malignant cervical tissue when compared to normal tissue. Expression of hENT mRNA was highly variable and not associated with malignancy. We also examined the effect of dFdU on gemcitabine disposition, as this relatively inactive metabolite is present at much higher concentrations in the plasma than gemcitabine following intravenous administration of the parent compound. We report a novel interaction between dFdU and gemcitabine whereby dFdU competes with gemcitabine for transport via hENT1 and hENT2. The presence of dFdU appears to enhance the retention of gemcitabine intracellularly leading to an increase in the amount of active gemcitabine triphosphate. As more gemcitabine is phosphorylated in the presence of dFdU, a "metabolic sink" is created, further increasing gemcitabine uptake into the cell via hENT1 and hENT2. These data suggest that both transport and intracellular metabolism are equally important components of gemcitabine disposition and cytotoxic potential, and that the presence of dFdU increases intracellular exposure to this nucleoside analog.