| Summary: | 碩士 === 國立陽明大學 === 藥理學研究所 === 92 === The complex pharmacological activities of thalidomide have again attracted lots of research interests in the biomedical field, and its clinical application has extended to numbers of carcinoma or immune disorders which were hard to cure before. However, previous relevant reports for the pharmacokinetic studies of thalidomide were restricted in the studies on oral route due to its poor water solubility, and there is no report on pharmacokinetic study on its unbound form. Therefore, in the present study, microdialysis sampling technique coupled with HPLC-UV was used to study the pharmacokinetics of unbound thalidomide in the blood, brain and bile after intravenous administration of thalidomide (1, 3 and 10 mg/kg) to Sprague Dawley rats. The results showed the Cmax in brain and bile was reached before 20 min, indicating fast concentration equilibrium of thalidomide in brain and bile with systemic circulation. Among all test doses, the concentration-time curves of blood, brain and bile were almost parallel to each other, indicating that the extents of concentration change with time in all sampling sites were similar. MRT and t1/2 in blood were statistically not different to those of brain and bile, suggesting elimination time in all sampling sites were unity. The blood AUC was proportional to the doses, suggesting a linear pharmacokinetics of unbound thalidomide. The extent of systemic unbound thalidomide distributed to brain and bile, defined as AUCbrain/AUCblood and AUCbile/AUCblood were 0.82-0.86 and 1.13-1.60, respectively. Furthermore, all these distribution ratios in each site were the same among different doses.
Cyclosporine has been used extensively as an immunosuppressive agent for transplant rejection and immune diseases. Cyclosporine combined with thalidomide has effectively treated some disorders, such as heart transplant rejection and Behcet''s disease. However, no study has reported whether cyclosporine can alter the pharmacokinetics of thalidomide in such combined use or not. Therefore, the interaction of cyclosporine (10 mg/kg) with thalidomide (3 and 10 mg/kg) was studied. In cyclosporine treated group, the blood pharmacokinetics of thalidomide still was linear. All pharmacokinetic parameters for 10 mg/kg thalidomide were not significantly changed except that blood MRT, t1/2 and bile MRT were slightly prolonged. For 3 mg/kg thalidomide, only slight increases in brain AUC and Cmax or bile t1/2 and MRT were observed. In addition, the AUCbrain/AUCblood and AUCbile/AUCblood for thalidomide (3 and 10 mg/kg) were not significantly changed by cyclosporine. In summary, cyclosporine appeared to have no obvious effect on the pharmacokinetic of thalidomide. Since cyclosporine is a P-glycoprotein inhibitor, these data suggest that P-glycoprotein may play no important role in the pharmacokinetics of thalidomide.
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