Diclofenac plasma protein binding: PK-PD modelling in cardiac patients submitted to cardiopulmonary bypass

Twenty-four surgical patients of both sexes without cardiac, hepatic, renal or endocrine dysfunctions were divided into two groups: 10 cardiac surgical patients submitted to myocardial revascularization and cardiopulmonary bypass (CPR), 3 females and 7 males aged 65 +/- 11 years, 74 +/- 16 kg body weight, 166 +/- 9 cm height and 1.80 +/- 0.21 m(2) body surface area (BSA), and control, 14 surgical patients not submitted to CPB, 11 female and 3 males aged 41 +/- 14 years, 66 +/- 14 kg body weight, 159 +/- 9 cm height and 1.65 +/- 0.16 m(2) BSA (mean +/- SD), Sodium diclofenac (1 mg/kg, im Voltaren 75(R) twice a day) was administered to patients in the Recovery Unit 48 h after surgery. Venous blood samples were collected during a period of 0-12 h and analgesia was measured by the visual analogue scale (VAS) during the same period, Plasma diclofenac levels were measured by high performance liquid chromatography. A two-compartment open model was applied to obtain the plasma decay curve and to estimate kinetic parameters, Plasma diclofenac protein binding decreased whereas free plasma diclofenac levels were increased five-fold in CPB patients. Data obtained for analgesia reported as the maximum effect (EMAX) were: 25% VAS (CPB) vs 10% VAS (control), P<0.05, median measured by the visual analogue scale where 100% is equivalent to the highest level of pain. To correlate the effect versus plasma diclofenac levels, the E(MAX) sigmoid model was applied. A prolongation of the mean residence time for maximum effect (MRTE(MAX)) was observed without any change in lag-time in CPB in spite of the reduced analgesia reported for these patients, during the time-dose interval, In conclusion, the extent of plasma diclofenac protein binding was influenced by CPB with clinically relevant kinetic-dynamic consequences.