Detail Role of albumin in tolbutamide metabolism by liver microsomes Bibliografi Author: Wang, Bing ; Ludden, Thomas M. (Advisor) Topik: HEALTH SCIENCES; PHARMACOLOGY|HEALTH SCIENCES; PHARMACY Bahasa: (EN )    ISBN: 0-599-52406-5     Penerbit: UNIVERSITY OF NEBRASKA MEDICAL CENTER     Tahun Terbit: 1999     Jenis: Theses - Dissertation Fulltext: 9950431.pdf (0.0B; 1 download) Abstract The ultimate goal of pre-clinical drug metabolism studies is to provide information predictive of the clinical situation. Successful in vitro - in vivo correlation requires accurate estimations of enzyme kinetic parameter values from in vitro drug metabolism data. Albumin is synthesized in the liver and nearly 67% albumin exists extracellularly. Therefore, to mimic the in vivo situation, albumin was introduced to the in vitro drug metabolism incubation medium. In this work, tolbutamide (TOL) was chosen as the model drug to investigate the effect of albumin in in vitro drug metabolism. Human or rat liver microsomes were incubated at 37°C with TOL and an NADPH generating system in the absence and presence of albumin (bovine, human and rat). It was found that in all cases, the presence of albumin induced a marked decrease in the free KM estimate while Vmax value was unaltered. Isothermal titration calorimetry study revealed an exothermic and saturable interaction between albumin and liver microsomes. In addition, the low affinity binding of TOL to albumin seemed to be completely lost when 1 mg protein/mL liver microsomes were present. Furthermore, the presence of 4% albumin in the incubation medium gave better prediction of the in vivo hepatic clearance of tolbutamide in rats. An albumin-facilitated delivery mechanism was proposed to explain the effect of albumin on TOL microsomal metabolism. This mechanism and the inference that the presence of albumin in the incubation medium gives better in vitro - in vivo correlation is still subject to future investigations with substrates of cytochrome P450 isozymes other than CYP2C9, and compounds that are not highly protein bound in the serum. Opini Anda Klik untuk menuliskan opini Anda tentang koleksi ini! Lihat Sejarah Pengadaan  Konversi Metadata   Kembali

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