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Effects of Fix 6,7-furocoumarins on the Hepatic Microsome Cytochrome P2C9, 2C19 Activity in Rats

Author: LiJuCang
Tutor: WangDeCai
School: Taishan Medical College
Course: Pharmacology
Keywords: 6,7-Furocoumarin compounds Liver microsomes Cytochrome P450 2C9 Cytochrome P4502C19 Inhibition Phenytoin Propranolol
CLC: R965
Type: Master's thesis
Year: 2011
Downloads: 19
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Abstract


ObjectiveTo investigate the effect of six 6,7-furocoumarin compounds (psoralen, Isopimpinellin, xanthotoxol, xanthotoxin, imperatorin and isoimperatorin) on liver microsomal cytochrome P4502C9, 2C19 activity in rat,and calculate the half inhibitory concentration IC50. To investigate the effect of pharmacokinetic parameters of phenytoin and propranolol which are metabolismed by CYP2C9 and CYP2C19 given by Total Coumarins from Radix Angelicae Dahuricae (TCD) at the results of in vitro metabolism.Method①Adopt healthy adult male Wistar and rats liver enzyme activity were induced by phenobarbital. Rat liver microsomes were prepared by CaCl2 precipitation method, and the total protein content and CYP and cytochrome b5 (Cytb5) were measured.②six 6,7-furocoumarin compounds or positive control drug chloramphenicol were added in 500μl reaction system in vitro, the final concentration were 1.0, 2.0, 4.0, 8.0, 16.0 and 32.0μg·mL-1, at the same time established control group; joined the probe drugs tolbutamide (CYP2C9) or mephenytoin (CYP2C19) in each tube for hatching reaction. The final concentration of 4-OH-tolbutamide and 4-OH-mephenytoin which were the metabolites of two probes in the reaction system in vitro were detected by HPLC. And the IC50 was calculated to investigate the six 6,7-furocoumarin compounds in inhibitory effect on rat liver microsomal CYP2C9 and 2C19 activity.③16 healthy male rats were divided randomly into two groups. Test drug group (Ⅱ) intragastric administration 50.0mg·kg-1 TCD once a day for 3 days; The control group (Ⅰ) were given the same volume of saline. Each group was given phenytoin 50mg·kg-1 after 1 h at the last time given TCD and Cut tail draws blood after 1,2,3,4,5,7,9,12,15,20 and 25h after the treatment. To detect plasma dilantin sodium concentrations used High performance liquid chromatographic and calculated pharmacokinetic parameters.④16 healthy male rats were divided randomly into two groups. Test drug group (Ⅱ) intragastric administration 50.0 mg·kg-1 TCD once a day for 3 days; The control group (Ⅰ) were given the same volume of saline. Each group was given propranolol 10 mg·kg-1 after 1 h at the last time given TCD and Cut tail draws blood after 0.33,0.66,1,1.5,2,3,4,5,7,9, 11h after the treatment. To detect plasma propranolol concentrations used High performance liquid chromatographic and calculated pharmacokinetic parameters.Results①The phenobarbital-induced rat liver microsomal protein content was 20.08mg·g-1Liver wet, CYP and Cytb5 were 0.51 and 0.346nmol·mg-1Protein. And CYP enhanced 21.38% compared to the normal control group.②six concentrations of chloramphenicol were strongly inhibited production quantity of the 4-OH-tolbutamide and 4-OH-mephenytoin, and were fitted well in a dose-dependent manner. The IC50 of CYP2C9: psoralen (5.26), imperatorin (7.15), xanthotoxol (21.88) isoimperatorin (31.25), Isopimpinellin (40.76) , xanthotoxin (52.95) and chloramphenicol (0.33); the IC50 value of CYP2C19: psoralen (5.40), imperatorin (9.82), xanthotoxol (41.57), isoimperatorin (15.37), Isopimpinellin (94.78), xanthotoxin (89.45) and chloramphenicol (0.55).③The main pharmacokinetic parameters of phenytoin: The control group(Ⅰ)Ka(0.22h-1)、Ke(0.10h-1)、t1/2α(2.31h)、t1/2β(7.62h)、AUC(314.63μg·h·mL-1)、CL(0.16 L·h-1)、Tpeak(5.64h)和Vd(0.99 L·kg-1); Test drug group(Ⅱ)Ka(0.27h-1)、Ke(0.06h-1)、t1/2α(2.31h)、t1/2β(13.46h)、AUC(457.83μg·h·mL-1)、CL(0.11L·h-1)、Tmax(6.37h)和Vd(1.06 L·kg-1)。After the combination of TCD,the elimination rate constant (Ke) significantly reduced, clearance rate(CL) obviously decreased, the area under the curve( AUC) increased significantly.④Two groups main pharmacokinetic parameters of propranolol: The control group(Ⅰ)Ka(1.95h-1)、Ke(0.16h-1)、t1/2α(0.36h)、t1/2β(4.59h)、AUC(690.70μg·h·mL-1)、CL(14.98L·h-1)、Tmax(1.41h)和Vd(95.11L·kg-1); Test drug group(Ⅱ)Ka(1.94h-1)、Ke(0.13h-1)、t1/2α(0.38h)、t1/2β(5.67h)、AUC(851.08μg·h·mL-1)、CL(12.43L·h-1)、Tmax(1.41h)和Vd(94.92L·kg-1). After the combination of TCD ,the elimination rate constant (ke) significantly reduced, clearance rate(CL) obviously decreased, the area under the curve( AUC) increased significantly.Conclusions①Hepatic microsome induced by phenobarbital which was prepared by the CaCl2 precipitation method CYP content was increased,and fully meet the needs of drug metabolism studies in vitro.②Psoralen and imperatorin were moderate inhibition on rat liver microsomal CYP2C9 and CYP2C19 activity. Other coumarin compounds were still weak inhibition, IC50 is less than 100μmol·L-1. Approximate order of CYP2C9 inhibition: psoralen≥imperatorin > xanthotoxol > isoimperatorin > Isopimpinellin > xanthotoxin; Approximate order of CYP2C19 inhibition: psoralen > imperatorin > isoimperatorin > xanthotoxol > xanthotoxin≥Isopimpinellin.③TCD can significantly decrease phenytoin metabolism in rats.④TCD can significantly decrease propranolol metabolism in rats.

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