PARACETAMOL PLASMA AND CEREBROSPINAL-FLUID PHARMACOKINETICS IN CHILDREN

Aims Paracetamol has a central action for both antipyresis and analges ia. Maximum temperature decrease and peak analgesia are reported at 1- 2 h after peak plasma paracetamol concentration. We wished to determin e the relationship between plasma and cerebrospinal fluid (CSF) pharma cokinetics in children. Methods; Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40 mg kg(-1) were measured in n ine children who had indwelling ventricular drains. Estimation of popu lation pharmacokinetic parameters was made using both a standard two-s tage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70 kg person using an allomet ric power model. Results Both approaches gave similar estimates. NONME M parameter estimates were clearance 10.21 h(-1) (CV 47%), volume of d istribution 67.11 (CV 58%) and absorption rate constant 0.77 h(-1) (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasm a. The equilibration half time was 0.72 h (CV 117%). The CSF/plasma pa rtition coefficient was 1.18 (CV 8%). Conclusions Higher concentration s in the CSF probably reflect the lower free water volume of plasma. T he CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time i s required for paracetamol to exert its effects. Effect site concentra tions equilibrate slowly with plasma. Paracetamol should be given 1-2 h before anticipated pain or fever in children.