Dissertation
Dissertation > Medicine, health > Pharmacy > Pharmacology

The Pharmacokinetic and Therapeutic Effects on Metabolic Syndrom of Recombinant Human Ciliary Neurotrophic Factor Analogs

Author CuiMingXia
Tutor ZhengRongLiang
School Lanzhou University
Course Cell Biology
Keywords recombinant human ciliary neurotrophic factor (rhCNTF) pharmacokinetic obesity diabetes mellitus nonalcoholic fatty liver disease (NAFLD) insulin resistance metabolic syndrome free fatty acid (FFA) cytochrome P450 2E1 (CYP2E1) antioxidative activity malodialdehyde (MDA) nitric oxide (NO) Alanine Aminotransferase (ALT) stearoyl-coenzyme A desaturase-1 (SCD-1) carnitine palmitoyltransferase-1 (CPT-1) body weight rebound gain conditioned taste aversion
CLC R96
Type PhD thesis
Year 2009
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ⅠTherapetic effects on metabolic syndrome of recombinant human ciliary neurotrophic factor (rhCNTF) analogsAbdominal obesity is the dominant underlying risk factor for metabolic syndrome and links with insulin resistance,type 2 diabetes,and coronary heart disease tightly.Each factor in metabolic syndrome is the risk factor for coronary heart disease,so therapy on metabolic syndrome is a whole concept of diagnosis and treatment of a group of high-related diseases.Loss of body weight,reduction of blood glucose and pressure,and blood lipid regulation are all same important.This experiment is to prepare models of diet-induced obesity,diabetes mellitus obesity,nonalcoholic fatty liver disease,and metabolic syndrome in rats or mice and to study the influence of rhCNTF analogs on activity of stearoyl-coenzyme A desaturase-1(SCD-1) and camitine palmitoyltransferase-1(CPT-1) and on free radical formation,blood level and expression of CYP2E1.The results will provide the theoretical basis for clinical therapy of obesity,nonalcoholic fatty liver disease,and metabolic syndrome with recombinant human ciliary neurotrophic factor(rhCNTF) analogs(C-16 and rhmCNTF).The results showed that animal models had obesity,visceral adipose accumulation, blood lipid abnormality,hyperglycemia,hyperinsulinemia,insulin resistance,and hepatic steatosis.The two analogs of rhCNTF both significantly decreased body weight and fat content with dose-dependent manner.This effect was weakened after 8-9 days of treatment and correlated with changes of food intake.The body weight had no rapidly rebound after treatment cessation and obviously lower than blank group after 3 weeks of treatment cessation.The analogs of rhCNTF also ameliorated glucose and lipid metabolism abnormality,and enhanced insulin sensitivity.In addition,after treatment of rhCNTF analogs,hepatic steatosis and function of model animals were ameliorated and antioxidative activity of liver was enhanced.The expression of CPT-1 in liver was promoted,and SCD-1 and CYP 2E1 were inhibited. Furthermore,rhCNTF analogs had not cause conditioned taste aversion or stress response like short-term excessive food restriction when rats were administered a dose known to produce significant weight loss.The analogs of rhCNTF showed good theraputic effects on metabolic syndrome in animal model.It suggests that rhCNTF analogs have important clinical therapy value on metabolic syndrome. ⅡPharmacokinetics of recombinant human ciliary neurotrophic(rhCNTF) analogur C-16To study pharmacokinetic property of recombinant human ciliary neurotrophic factor(rhCNTF) analogue C-16 after intravenous(i.v.) and subcutaneous(s.c.) injection to mice,rats,or monkeys.Double antibody sandwich ELISA analysis was used for testing drug concentration in serum,bile,urine,and tissues.Pharmacokinetic parameters were calculated by DAS software.The results showed that:1.The specificity and sensitivity of rhCNTF assay kit were high.The detection limit was 0.0625 ng/ml and the linear range was within 0.0625-16 ng/ml(r2>0.9999). The detection limit of C-16 in biological media was 0.5 ng/ml and the linear range was within 0.5-32 ng/ml(r2>0.9997).2.Pharmacokinetic property of C-16 in rats after i.v.300μg/kg was consistent with two-compartment open model and first-order kinetic elimination.The main pharmacokinetic parameters were as follows:t1/2β:1.39 h,CL:0.036 L/h/kg,Vd:0.20 L/kg,AUC0-6:8580μg/L·h,AUC0-∞:9006μg/L·h.Pharmacokinetic property of C-16 in rats after s.c.100,300,and 900μg/kg were consistent with one-compartment open model.Cmax:10.8,202.0 and 508.7μg/L,AUC0-t:42.2,876.5 and 1810.6μg/L·h, AUC0-∞:46.4,939.8 and 2072.1μg/L·h,Tmax:1.35,0.65 and 0.75 h,t1/2:1.94,2.33 and 2.90 h,CL/F:2.23,0.33 and 0.54 L/h/kg,MRT0-t:2.82,3.25 and 3.15 h,MRT0-∞: 3.88,3.61 and 4.09 h,respectively.Bioavailability of C-16 s.c.in rats:10.4%.3.Pharmacokinetic property of C-16 in monkeys after i.v.300μg/kg was consistent with two-compartment open model and first-order kinetic elimination.The main Pharmacokinetic parameters were as follows:t1/2α:2.39 h,CL:0.064 L/h/kg,Vd: 0.302 L/kg,AUC0-6:2438μg/L·h,AUC0-∞:2553μg/L·h.Pharmacokinetic property of C-16 in monkeys after s.c.50,150,and 450μg/kg were consistent with one-compartment open model.Cmax:9.9,29.5 and 73.5μg/L,AUC0-t:58.8,157.8 and 491.9μ/L·h,AUC0-∞:66.4,174.1 and 540.9μg/L·h,Tmax:3.50,3.00 and 2.50 h,t1/2: 2.08,2.09 and 2.93 h,CL/F:1.10,0.93 and 0.89 L/h/kg,MRT0-t:4.07,4.04 and 5.26 h, MRT0-∞:5.52,5.54 and 7.59 h,respectively.Bioavailability of C-16 s.c.in monkeys: 6.82%.4.Distribution property of C-16 in mice:At 15 min after C-16 i.v.600μg/kg to mice,ovarian had the highest drug concentration.Fat and heart tissues took the second place.Live,kidney,thymus,and uterus tissues had middle level,while spleen、lung,muscle tissues had low level(less than 4%of that in serum).Drug had not been detected in brain,pancreas,and testis tissues.At 45 min,ovarian and fat tissues had the highest drug concentration.Kidney took the second place.Drug concentration was 25%in liver and uterus and was less than 20%in heart,lung,muscle,spleen,and thymus of that in serum concentration.Drug was low(5.07%of that in serum) in brain and had not detected in pancreas and testis.At 3 h,Drug concentration was still high in fat tissues(about two times than that in serum),was about 80%in kidney, ovarian,and uterus,and 50%in heart and liver of that in serum.Drug had not been detected in spleen,lung,brain,muscle,thymus,pancreas,and testis tissues.5.Elimination character of C-16 in urine:The total drug accumulative excretion ratio in urine was 4.24 per million during 36 h after i.v.600μg/kg and had not been detected after 1 h.6.Elimination character of C-16 in bile:The total drug accumulative excretion ratio in bile was 0.31%during 24 h after i.v.300μg/kg.In conclusion,pharmacokinetic models of C-16 are two-compartment open model and first-order kinetic elimination after i.v.and are one-compartment open model and first-order kinetic elimination after s.c.to rats and monkeys.The main pharmacokinetic parameters in the same genus animal are not significantly different. After balanced distribution,the concentration of C-16 in fat was the highest,which in ovarian,liver and kidney still maintained in high level,whilein in brain declined to low level,however which could not be detected in testis and pancreas.The excretion ratio of C-16 is very low in urine and bile.

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