Stereoselective propranolol metabolism in two drug induced rat hepatic microsomes  

作　　者：Li X Zeng S 

机构地区：[1]College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310031,China

出　　处：《World Journal of Gastroenterology》2000年第1期74-78,共5页世界胃肠病学杂志（英文版）

基　　金：the National Natural Science Foundation of China,No.39370805.

摘　　要：AIM To study the influence of inducers BNFand PB on the stereoselective metabolism ofpropranolol in rat hepatic microsomes.METHODS Phase Ⅰ metabolism of propranololwas studied by using the microsomes induced byBNF and PB and the non-induced microsome asthe control.The enzymatic kinetic parameters ofpropranolol enantiomers were calculated byregression analysis of Lineweaver-Burk plots.Propranolol concentrations were assayed byHPLC.RESULTS A RP-HPLC method was developed todetermine propranolol concentration in rathepatic microsomes.The linearity equations forR（+）-propranolol and S（-）-propranolol wereA=705.7C+311.2C（R = 0.9987）and A= 697.2C+311.4C（R = 0.9970）respectively.Recoveriesof each enantiomer were 98.9%,99.5%,101.0%at 60 μmol/L,120 μmol/L,240 μmol/Lrespectively.At the concentration level of120 μmol/L,propranolol enantiomers weremetabolized at different rates in differentmicrosomes.The concentration ratio R（+）/S（-）of control and PB induced microsomesincreased with time,whereas that of microsomeinduced by BNF decreased.The assayed enzymeparameters were:1.Km.Control group:R（+）30+₈,S（-）18+₅;BNFgroup:R（+）34+3,S（-）39±7;PB group:R（+）38±17,S（-）36±10.2.Vmax.Control group:R（+）1.5+0.2,S（-）2.9±0.3;BNF group:R（+）3.8±0.3,S（-）3.3±0.5;PB group:R（+）0.07±0.03,S（-）1.94±0.07.3.Clint.Control group:R（+）60±3,S（-）170±30;BNF group:R（+）111.0±1,S（-）84± 5;PBgroup:R（+）2.0±2,S（-）56.0±1.Theenzyme.parameters compared with unpaired ttests showed that no stereoselectivity wasobserved in enzymatic affinity of threemicrosomes to enantiomers and their catalyticabilities were quite different and hadstereoselectivities.Compared with the control,microsome induced by BNF enhanced enzymeactivity to propranolol R（+）-enantiomer,andmicrosome induced by PB showed less enzymeactivity to propranolol S（-）-enantiomer whichremains the same stereoselectivities as that ofthe control.CONCLUSION Enzyme activity centers AIM:To study the influence of inducers BNF and PB on the stereoselective metabolism of propranolol in rat hepatic microsomes.METHODS:Phase I metabolism of propranolol was studied by using the microsomes induced by BNF and PB and the non induced microsome as the control.The enzymatic kinetic parameters of propranolol enantiomers were calculated by regression analysis of Lineweaver-Burk plots. Propranolol concentrations were assayed by HPLC.RESULTS:A RP-HPLC method was developed to determine propranolol concentration in rat hepatic microsomes. The linearity equations for R(+)propranolol and S(-) propranolol were A = 705.7C+311.2C (R = 0.9987) and a = 697.2C+311.4C (R = 0.9970) respectively. Recoveries of each enantiomer were 98.9%, 99.5%, 101.0% at 60&mgr;mol/L, 120&mgr;mol/L, 240&mgr;mol/L respectively. At the concentration level of 120&mgr;mol/L, propranolol enantiomers were metabolized at different rates in different microsomes. The concentration ratio R(+)/S(-) of control and PB induced microsomes increased with time, whereas that of microsome induced by BNF decreased. The assayed enzyme parameters were: 1. Km. Control group: R(+)30 plus minus 8, S(-)18 plus minus 5; BNF group: R(+)34 plus minus 3, S(-)39 plus minus 7; PB group: R(+)38 plus minus 17, S(-)36 plus minus 10. 2. Vmax. Control group: R(+)1.5 plus minus 0.2, S(-)2.9 plus minus 0.3; BNF group: R(+)3.8 plus minus 0.3, S(-)3.3 plus minus 0.5; PB group: R(+)0.07 plus minus 0.03, S(-)1.94 plus minus 0.07. 3. Clint. Control group: R(+)60 plus minus 3, S(-)170 plus minus 30; BNF group: R(+)111.0 plus minus 1, S(-) 84 plus minus 5; PB group: R(+)2.0 plus minus 2, S(-)56.0 plus minus 1. The enzyme parameters compared with unpaired t tests showed that no stereoselectivity was observed in enzymatic affinity of three microsomes to enantiomers and their catalytic abilities were quite different and had stereoselectivities.Compared with the control, microsome induced by BNF enhanced enzyme activity to propranolol R(+)enantiomer, and microsome induce

关 键 词：Subject headings PROPRANOLOL enantiomers RAT HEPATIC MICROSOME PHENOBARBITAL β-naphthoflavone 

分 类 号：R96[医药卫生—药理学]