Pharmacokinetics of a combination of Δ9‐Tetrahydro‐cannabinol and celecoxib in a porcine model of hemorrhagic shock

Abstract

Hemorrhagic shock involves loss of a substantial portion of circulating blood volume leading to diminished cardiac output and oxygen delivery to peripheral tissues. In situations where an immediate resuscitation cannot be provided, pharmacotherapy with a novel combination of Δ9-tetrahydro-cannabinol (THC) and celecoxib (CEL) is currently investigated as an alternative strategy to prevent organ damage. In the present study, 28 Yorkshire×Landrace pigs were used to study the pharmacokinetics of THC and CEL in an established porcine model of hemorrhagic shock. Pigs in hemorrhagic shock received 0.5, 1 or 4 mg/kg THC and 2 mg/kg CEL, while normotensive pigs received 1 mg/kg THC and 2 mg/kg CEL by intravenous injection. THC and CEL plasma concentrations were simultaneously determined by LC-MS/MS. Pharmacokinetic parameters and their between animal variability were obtained using standard non-compartmental analysis as well as a compartmental analysis using nonlinear mixed effects modeling. The concentration-time profiles of THC and CEL followed a multi-exponential decline and their pharmacokinetics were similar in hemorrhagic shock and normotensive conditions, despite the substantial change in hemodynamics in the animals with shock. This interesting finding might be due to the pharmacologic effect of the THC/CEL combination, which is intended to maintain adequate perfusion of vital organs in shock. Overall, this study established THC and CEL pharmacokinetics in a porcine shock model and provides the basis for dose selection in further studies of THC and CEL in this indication.