| The individual immunosuppressant dosage regimen of Organ transplant recipients after transplantation is directly related to the survival of the transplanted organ.Tacrolimus (FK506) to be life-long immunity medication as first-line drug for liver transplant recipients. However, the drug's pharmacokinetics existing large individual differences and its narrow therapeutic index, and its dose-effect relationship has many influencing factors, report from abroad claimed that a heart transplant recipient coadministrated FK506 and clarithromycin (CLA) could improve the blood steady state concentration of FK506. Becasuse of the two drugs metabolize both in P450 enzyme system ,to improve the quality life of recipients, safe, effective and economic use drug individually, researching pharmacokinetics has great significance.Currently, the research of FK506 at home and abroad is focused on the study of many transplant recipients within one year after transplantation. To the recipients who's survival time are more than a year, FK506 dose-effect relationship and the interaction between FK506 and CLA, study is less.The topic for the liver transplant recipients after more than a year, to study the long-term administration of FK506, dose-effect relationship and its influencing factors. And applying high performance liquid chromatography (HPLC) to monitor the chromatographic peak of FK506 and CLA. This study will do good experimental foundation laid for the research of the pharmacokinetics interaction between the two drugs.Objective: Liver transplant recipients after more than a year, and who considered FK506 as the main immune drug treatment are included. For the study to explore the dose-effect relationship of FK506 after long-term administration of it. Inspecting the reasonableness of FK506 plasma concentration reference value for laboratory applications. And setting up a suitable valley plasma concentration steady state value of the normal range for liver transplant recipients, in order to avoid rejection and toxic reactions. To provide experimental evidence for the drug use individually.Applying HPLC to monitor the chromatographic peak of FK506 and CLA. The study will lay the foundation for the interation between two drugs in human pharmacokinetic research.Methods:1 Follow-up liver transplantation recipients for more than one year after transplantation, and who is making long-term FK506 blood concentration monitoring in our hospital, recording gender, age, height,weight, biochemical index of liver function, dose of FK506 and concentration. Determinated blood concentration value of FK506 by MEIA. Analysis plasma concentration of FK506 in all liver transplantation recipients and the normal reference range in line with the rates, according to clinical symptom,toxic reaction and rejection to adjust to the normal reference range.2 By applying HPLC to determine FK506 and CLA.Results:1 24 cases included in the statistics of liver transplant recipients,≥1 year after transplantation have 8 cases(33.3%), there is 6 cases (25%)≥2 years, 7 cases (29.2%)≥3 years, and 3 cases(12.5%)≥4 years. A total of FK506 blood concentration monitoring are 154 cases. The results showed that≥1 year after transplantation,≥2 years,≥3 years,≥4 years, FK506 dosage were 0.035±0.010mg/kg/d, 0.061±0.032mg/kg/d, 0.043±0.013 mg / kg / d, 0.015±0.009 mg / kg / d; The corresponding plasma concentration values were 5.1±2.0ng/ml, 4.6±1.4 ng / ml, 3.7±1.3 ng / ml, 3.0±1.3 ng/ml. However, the coefficient correlation (r) between the dose and FK506 blood concentration values is only 0.08.Transplantation after the first three months and three months after, the blood concentration and the reference value in line is 42.0%, 51.3%, super-scope below the lower limit of the number of cases accounted for 55.0%, 31.9%,respectively. The coincidence of FK506 blood concentration of the reference value (three months after transplantation is 5ng/ml ~10ng/ml) is 26% in all 154 cases. and the rest are super-minimum. Between 3ng/ml~5ng/ml account for 50%. but there is no rejection and toxic reactions.2 The chromatographic conditions to determine FK506 by HPLC-DAD is: C8 column (Agilent Zorbax Eclipse XDB, 4.6mm×150mm, 5μm), a mobile phase of acetonitrile -0.25% phosphoric acid (60:40), column temperature 50℃, flow rate 1ml/min, detection wavelength 210nm, injection volume 10μl. Its standard curve equation was A=9.11C-14.56 (r=0.9999 n = 9). Within 1000μg/ml~ 6.25μg/ml scope, FK506 has a good linear relationship. Interday, intraday precision were <10%. Comply with the requirements of Pharmacopoeia(2005).3 Determination of CLA by HPLC-DAD as the stationary phase chromatographic conditions: octadecyl bonded silica (150mm×4.6mm,5μm); mobile phase: 0.067mol/L potassium dihydrogen phosphate - acetonitrile (60:40); wavelength 210nm, column temperature:30℃, flow rate 1.0ml/min, injection volume 20μl. Standard curve equation derived from is A=0.6098C+12.978, r=0.9999(n=7). Between 1000μg/ml~ 25μg/ml, CLA concentrations and peak area showed good linearity. Its interday and intraday precision were <10%, in line with the relevant provisions.Conclusion:1 The correlation between dose and blood concentration value of FK506 is poor. The rates to concentration of FK506 and dose (C/D) does not change regularly with time after transplantation. Transplantation after the first three months and three months after, the blood concentration values of FK506 in liver transplant recipients can be properly reduced, after more than 1 year, its blood concentration should be controlled at 3ng/mL~5ng/mL, the dose is also required varies from person to person.2 HPLC Determines FK506 and CLA is in stable way, which could be considered as foundation for pharmacokinetics interaction between the two drugs.
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