Study Of Cytochrome P450ⅢA Enzyme Activity In Acute Leukemia Of Children

【Objective】Application of midazolam as in-vivo probe of cytochrome P450ⅢA enzyme activity (CYP3A activity), comprehending interindividual variation and influential factors of hepatic CYP3A activity in acute leukemia of children, and exploring possibility of a single plasma sampling to estimate intravenous clearance midazolam and CYP3A activity.【Methods】Twenty one acute leukemia of children receiving a short i.v. bolus midazolam(dose,0.1mg/kg), blood samples were drawn at 15,30,60,120,240 and 360 minutes following administration of midazolam , and blood samples were collected in glass tubes containing heparin. And twelve acute lymphoblastic leukemia (ALL) of children receiving midazolam test before and after prednisone induction test. Midazolam concentrations in plasma were determined using liquid chromatography-mass spectrometry, and pharmacokinetic variables were calculated using compartmental analysis, calculating it's clearance and area under the curve,as a parameter of CYP3A activity.【Results】All thirty three midazolam test in 21 acute leukemia of children, no one child take places obviously adverse reaction. Respectivly minimal and maximal clearance of midazolam are 0.027 L/h/kg and 0.181 L/h/kg. CYP3A activity varies as much as 7-fold in liver of acute leukemia of children. Girls'clearance of midazolam (0.11±0.035 L/h/kg) were higher than boys'(0.073±0.025 L/h/kg)( P =0.014). Clearance of midazolam of acute non-lymphocytic leukemia of children (0.085±0.024 L/h/kg) were lower than acute lymphocytic leukemia of children (0.094±0.039 L/h/kg), but these were not statistically significant (P =0.641). Clearance of midazolam of acute lymphocytic leukemia of children after prednisone induction test were higher than before (0.140±0.057 L/h/kg vs 0.094±0.043 L/h/kg, P=0.037). Clearance of midazolam in children of liver functional lesion after chemotherapy were obviously lower than those of non-liver functional lesion (0.112±0.029 vs 0.208±0.07 L/h/kg,P=0.026) in nine high risk acute lymphoblastic leukemia of children receiving the same chemotherapy. A significant correlation(r =-0.718, r =0.916,respectivly) was found between the concentrations of midazolam measured 60 min after an IV dose and clearance of midazolam and area under the curve.【Conclusions】As an in-vivo probe of hepatic CYP3A activity, midazolam is secure and feasible in acute leukemia of children. Interindividual variation were obvious in hepatic CYP3A activity of acute leukemia of children, and girls'were higher than boys'. Oral prednisone could induce hepatic CYP3A in acute leukemia of children. Clearance of midazolam can be used to assess liver function in patients of acute leukemia. Single plasma sampling of 60min after 0.1mg/kg midazolam i.v. can be used to predict the intravenous clearance of midazolam and area under the curve of midazolam in acute leukemia of children , and it can be also used to be a parameter of CYP3A activity of acute leukemia of children.