Pharmacokinetics of paracetamol in adults after cardiac surgery

Abstract

The pharmacokinetics of paracetamol in adults after cardiac surgery have not been described. Twenty patients were randomized to receive either paracetamol 2 g through a nasogastric tube and as a suppository eight hours later or vice versa. Arterial blood samples were taken at 0.5, one, two, four, six and eight hours after dosing. Each patient was studied for 16 h. There were 16 males and three females. One patient was excluded because of sampling errors. The mean age was 59 (SD 8) years and the mean weight 84 kg (16). The time-concentration profiles for each individual were used to estimate pharmacokinetic parameters using a non-linear mixed effects model (NONMEM). Population parameter estimates with coefficient of variation (CV%), standardized to a 70 kg person, for a one-compartment model with first order input, lag time and first order elimination were volume of distribution 127 l (28) and clearance 26.4 l/h (29) Rectal paracetamol had an absorption half-life (T(abs)) of 2.02 h (31) with a lag time of 0.28 h. The absorption half-life for the oral preparation was 1.49 h (81) with a lag time of 0.17 h. The relative bioavailability of the rectal compared to the oral formulation was 0.98 (18). Concentrations after either nasogastric or rectal paracetamol 2 g were below a target concentration of 10 mg/l, which is associated with analgesia. Absorption after nasogastric administration was slow compared to healthy adults (T(abs) 0.06 to 0.7 h) and the bioavailability was half that expected, due to nasogastric loss. Parameter estimates had large variability. Paracetamol is unlikely to have useful clinical impact in the majority of patients when standard doses (6 g/day) are given on day 1 after cardiac surgery.