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|Title:||Pharmacology of Gemcitabine in the Asian Population||Authors:||WANG LINGZHI||Keywords:||Gemcitabine; dFdCTP; pharmacokinetics; pharmacodynamics;SNP; Patients||Issue Date:||13-Nov-2008||Citation:||WANG LINGZHI (2008-11-13). Pharmacology of Gemcitabine in the Asian Population. ScholarBank@NUS Repository.||Abstract:||Gemcitabine (dFdC) is a broad spectrum antimetabolite effective for treating several solid tumors. However, its complex disposition pathway and schedule dependence provides opportunity to investigate pharmacokinetic and pharmacodynamic interactions, including genetic determinants of these to optimize clinical use. In vitro titration using cell line model showed that exposure time to dFdC 10 uM and above determines the accumulation of the active intracellular gemcitabine triphosphate (dFdCTP). Using 2 different infusion rates of dFdC in NSCLC patients resulted in similar clinical efficacy and safety profile. Pharmacokinetic analyses of dFdC and dFdCTP suggested that 30-min infusion is pharmacologically less efficient than 75-min constant rate infusion in terms of dFdCTP accumulation. Pharmacokinetic-pharmacodynamic analysis showed that intracellular dFdCTP exposure predicted dFdC induced myelosuppression in the 30-min arm. Maximum concentration of dFdCTP was found to be a good predictor for neutropenia. Genetic variants in hCNT2 were identified as a potential determinant of neutropenia and patient survival.||URI:||http://scholarbank.nus.edu.sg/handle/10635/12909|
|Appears in Collections:||Ph.D Theses (Open)|
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