Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery

The pharmacokinetics of propranolol may be altered by hypothermic cardiopulmonary bypass (CPB), resulting in unpredictable postoperative hemodynamic responses to usual doses. The objective of the present study was to investigate the pharmacokinetics of propranolol in patients undergoing coronary artery bypass grafting (CABG) by CPB under moderate hypothermia. We evaluated 11 patients, 4 women and 7 men (mean age 57 ± 8 years, mean weight 75.4 ± 11.9 kg and mean body surface area 1.83 ± 0.19 m²), receiving propranolol before surgery (80-240 mg a day) and postoperatively (10 mg a day). Plasma propranolol levels were measured before and after CPB by high-performance liquid chromatography. Pharmacokinetic Solutions 2.0 software was used to estimate the pharmacokinetic parameters after administration of the drug pre- and postoperatively. There was an increase of biological half-life from 4.5 (95 percent CI = 3.9-6.9) to 10.6 h (95 percent CI = 8.2-14.7; P < 0.01) and an increase in volume of distribution from 4.9 (95 percent CI = 3.2-14.3) to 8.3 l/kg (95 percent CI = 6.5-32.1; P < 0.05), while total clearance remained unchanged 9.2 (95 percent CI = 7.7-24.6) vs 10.7 ml min-1 kg-1 (95 percent CI = 7.7-26.6; NS) after surgery. In conclusion, increases in drug distribution could be explained in part by hemodilution during CPB. On the other hand, the increase of biological half-life can be attributed to changes in hepatic metabolism induced by CPB under moderate hypothermia. These alterations in the pharmacokinetics of propranolol after CABG with hypothermic CPB might induce a greater myocardial depression in response to propranolol than would be expected with an equivalent dose during the postoperative period.

Simplified micromethod for the HPLC measurement of diclofenac in plasma

A simple and senmsitive micromethod based on HPLC is described for the measurement of diclofenac in 200 ul plasma. A single extraction with dichlormethane in acidic medium was an essential clean-up step. Diclofenac and its internal standard (cyclohexendiphenyl propionic acid) were eluted at 3.3 and 6.5 min from a 4-micron C18 reverse-phase column using a mobile phase consisting of 0.75 M sodium acetate buffer, pH 5.0, and acetonitrile (55:45, v/v) at a flow rate of 0.9 ml/min with detection at 282 nm. The method, validated on the basis of parameters evaluated nfor the confidence limits of diclofenac measurements in spiked plasma, presented 1 ng/ml sensitivity, 10-10,000 ng/ml linearity, and 3.5% and 5.7% intra-and interassay precision, respectively. Peak plasma diclofenac levels ranging from 177 to 841 ng/ml and from 276 to 1008 ng/ml were obtained for two slow-release formulations. A wide range (1 ng/ml-3 ug/ml) was observed for plasma diclofenac levels of volunteers during a 24-h study period