Pharmacokinetics of Gemcitabine
Pharmacokinetics of Gemcitabine
Gemcitabine (dFdC) is a prodrug that undergoes metabolism by cytidine deaminase to form an inactive metabolite, 2´,2´-difluorodeoxyuridine (dFdU). The pharmacokinetics of dFdC and dFdU have been studied; however, their disposition has never been evaluated in a patient with ascites. A patient with pancreatic cancer and malignant ascites was treated with dFdC 1500 mg/m over 150 minutes weekly for 3 weeks, repeated every 4 weeks. Serial plasma and ascites samples were obtained on weeks 1 and 2 of cycle 2. High-pressure liquid chromatography was used to quantify dFdC and dFdU in plasma and ascites. The systemic dispositions of dFdC and dFdU were similar to those reported in patients without ascites. The concentration of dFdC in ascites approached 1 mg/ml. Ascitic fluid did not serve as a depot for dFdC, and the agent's concentration in ascites approached that at which its phosphorylation is saturated.
Gemcitabine (2´,2´-difluorodeoxycytidine; dFdC) is a prodrug that is rapidly metabolized. It is converted by cytidine deaminase to the inactive metabolite 2´,2´-difluorodeoxyuridine (dFdU). The agent also is metabolized intracellularly by deoxycytidine kinase to its active dFdC 5´-diphosphate (dFdCDP) and 5´-triphosphate (dFdCTP) forms. The pharmacokinetics of dFdC and dFdU have been described in patients with normal hepatic and renal function. Similar studies were performed in patients with impaired hepatic or renal function so that appropriate dosing recommen-dations could be made for such patients. This information was relevant because dFdC is approved for treatment of pancreatic carcinoma and has documented activity in patients with carcinoma of the bladder. Despite these studies, the pharmacokinetics of dFdC have not been described in a patient with ascites. This clinical condition is known to occur in patients with pancreatic cancer as well as other tumor types against which dFdC has clinical activity and is known to produce significant perturbations in the pharmacokinetics of a number of antineoplastic agents, such as methotrexate. The ability to perform pharmacokinetic studies of dFdC and its metabolites in a patient with ascites allowed us to address this issue.
Gemcitabine (dFdC) is a prodrug that undergoes metabolism by cytidine deaminase to form an inactive metabolite, 2´,2´-difluorodeoxyuridine (dFdU). The pharmacokinetics of dFdC and dFdU have been studied; however, their disposition has never been evaluated in a patient with ascites. A patient with pancreatic cancer and malignant ascites was treated with dFdC 1500 mg/m over 150 minutes weekly for 3 weeks, repeated every 4 weeks. Serial plasma and ascites samples were obtained on weeks 1 and 2 of cycle 2. High-pressure liquid chromatography was used to quantify dFdC and dFdU in plasma and ascites. The systemic dispositions of dFdC and dFdU were similar to those reported in patients without ascites. The concentration of dFdC in ascites approached 1 mg/ml. Ascitic fluid did not serve as a depot for dFdC, and the agent's concentration in ascites approached that at which its phosphorylation is saturated.
Gemcitabine (2´,2´-difluorodeoxycytidine; dFdC) is a prodrug that is rapidly metabolized. It is converted by cytidine deaminase to the inactive metabolite 2´,2´-difluorodeoxyuridine (dFdU). The agent also is metabolized intracellularly by deoxycytidine kinase to its active dFdC 5´-diphosphate (dFdCDP) and 5´-triphosphate (dFdCTP) forms. The pharmacokinetics of dFdC and dFdU have been described in patients with normal hepatic and renal function. Similar studies were performed in patients with impaired hepatic or renal function so that appropriate dosing recommen-dations could be made for such patients. This information was relevant because dFdC is approved for treatment of pancreatic carcinoma and has documented activity in patients with carcinoma of the bladder. Despite these studies, the pharmacokinetics of dFdC have not been described in a patient with ascites. This clinical condition is known to occur in patients with pancreatic cancer as well as other tumor types against which dFdC has clinical activity and is known to produce significant perturbations in the pharmacokinetics of a number of antineoplastic agents, such as methotrexate. The ability to perform pharmacokinetic studies of dFdC and its metabolites in a patient with ascites allowed us to address this issue.
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