| Summary: | 碩士 === 國立成功大學 === 臨床藥學研究所 === 90 === Introduction. Methylglyoxal-bis-guanylhydrazone (MGBG) is an antiproliferative agent. The structure of MGBG is similar to polyamines and it inhibits the biosynthesis pathway of polyamines. Studies on the pharmacokinetics of MGBG are rare. Due to its long half-life, initial clinical studies using once daily regimen showed severe toxicity of MGBG in patients. MGBG distributed widely into the body, especially in the liver. However, there are no reports on the hepatic extraction and disposition of MGBG, and the extent of its plasma protein binding remains unknown. To address all these issues, a simple and sensitive assay for MGBG in biological fluids is needed.
Objectives. The aim of this study is to develop a simple, rapid, and sensitive high-performance liquid chromatography (HPLC) method to quantitate the concentration of MGBG in plasma; to determine the unbound fraction of MGBG in plasma using ultrafiltration, and examining the effects of physiologic factors on the protein binding of MGBG; to characterize the disposition of MGBG in isolated perfused rat liver; and to investigate the pharmacokinetics of MGBG in rats.
Results. A new validated HPLC method for the analysis of MGBG in plasma was developed, and was applied successfully to pharmacokinetic studies. Binding of MGBG to plasma proteins is low with an unbound fraction greater than 77%, and is constant within the concentration range (0.5-50 mg/mL) studied. The unbound fraction decreased as the concentration of serum albumin increased from 0.1 to 4 %. The extent of protein binding increased with the increase of the pH of plasma, and a linear relationship was found between binding and the percentage of un-ionized form of MGBG in plasma. The hepatic extraction ratio of MGBG is low. The disposition kinetics of MGBG in the liver was permeability-rate limited and showed dose-dependency, suggesting that hepatic uptake of MGBG could be carrier-mediated. The disposition of MGBG in rats displayed two-compartmental characteristics, and its clearance was dose-dependent.
Conclusion. In summary, the binding of MGBG to plasma protein is low. As the hepatic extraction of MGBG is low, it seems that the major elimination organ is kidney. The clearance of MGBG in rats is dose-dependent, thus one should be very careful when adjusting the dosage of MGBG to avoid its accumulation.
|
|---|
