Pharmacokinetics and pharmacodynamics of indomethacin: effects on cerebral blood flow in anaesthetized sheep.

1. Indomethacin has been used to manage raised intracranial pressure (ICP) in humans during neuroanaesthesia and neurosurgery. Indomethacin causes cerebral vasoconstriction and reduces cerebral blood flow (CBF) and, therefore, ICP. 2. The systemic kinetics, cerebral kinetics and cerebral dynamics of indomethacin (0.2 mg/kg) were measured and modelled using a population approach. Data were collected using an instrumented sheep preparation with raised ICP and under either isoflurane or propofol anaesthesia to parallel the clinical use of indomethacin in neurosurgery. 3. The systemic kinetics of indomethacin could be described by a two-compartment model, with small distribution volumes and a clearance of 0.68 L/min. The cerebral kinetics of indomethacin could be described using a model with a cerebral distribution volume between 5 and 8 mL and a loss term of 3.3 mL/min, the latter probably representing slow diffusion across the blood-brain barrier. 4. The changes in CBF lagged behind the blood concentrations of indomethacin. Indirect response models with turnover times of 1.70-4.08 min were generally better able to describe the effect of indomethacin on CBF than effect compartment models. 5. There was a non-linear concentration-effect relationship, with the maximum possible reduction in CBF being to 73-74% of baseline. 6. The data and model support the concept of indomethacin having limited uptake into the brain, with its effect on CBF being the result of its action on the endothelium, where it indirectly modifies the turnover of a compound regulating vascular tone.