Studies On Pharmacokinetics Of Hemay014 In The Rat

AIM: To establish a high performance liquid chromatography (HPLC) method for determing the active metabolite thalidomide of prodrug hemay014. And to study on pharmacokinetics, absorption, distribution, and excretion of the metabolite thalidomide following administration of hemay014 in rats.METHODS: The concentration of the metabolite thalidomide in biological specimens was detected by a high performance liquid chromatography method. The obtained data were processed with"3P97"pharmacokinetics program.RESULTS: Both intra-day and inter-day precision were less than 10%, and the limit of detection was 0.6 ng. At the range with 0.2~20μg·ml-1 of thalidomide, there was a linear relationship with a value for R2 = 0.9996. All the mean recovery of thalidomide in plasma, tissues, bile, urine, and feces were more than 80%, so was the internal standard in plasma. Plasma sample could keep stability at room temperature for 6 h and at 4℃, -20℃for one week. The disposition was conformed to a two compartment model with t1/2α= 1.48～2.8 min, t1/2β= 167～178 min, Vd = 0.87～1.06 L·kg-1, CLs = 0.0036~0.0044 L·kg-1·min-1 after a single iv administration with 10 mg·kg-1 of hemay014. The disposition was conformed to a one compartment model with Tp = 29～100 min, t1/2ka = 5.0～32 min, t1/2ke = 206～570 min, F = 31%～74% after a single ig administration with hemay014. AUC, FX0, and Cmax of thalidomide increased proportionally with the dosages. Comparison with thalidomide ig administration, the metabolite thalidomide had a better F, a bigger FX0 and a higher Cmax in rats. There was rarely difference between female and male rats on basic pharmacokinetics. After administration of hemay014, the metabolite thalidomide was shown to be widely distributed to the various tissues. There was a relatively higher drug concentration in liver, intestine, kidney and brain. Thalidomide excreted in feces and urine was 0.23% in total within 24h. And almost no excretion was found in bile.CONCLUTIONS: The HPLC assay may be a constant, sensitive, accurate and specific method to detect the metabolite thalidomide. There was rarely difference between female and male rats on basic pharmacokinetics. After intravenous injection with hemay014, the metabolite thalidomide distributed rapidly and widely and eliminated slowly in rats. Plasma concentration-time profiles for metabolite thalidomide conformed to two-compartment model with first order absorption; after intragastric administration with hemay014, the metabolite thalidomide was absorpt and eliminated at a slow rate and bioavailability was good in rats. Plasma concentration-time profiles for metabolite thalidomide conformed to one-compartment model with first order absorption; about 0.23% of unchanged thalidomide was excreted in urine and feces, and almost no excretion was found in bile.