Influence of Escherichia coli Endotoxin on the Pharmacokinetics and Respiratory Depressant Effect of Alfentanil in Rabbits

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Abstract
Postoperative fever occurs in many surgical patients, due to release of pyrogens into the circulation. Pyrogens and fever may influence the pharmacokinetics and effects of drugs. The aim of this study was to investigate the interactions of a pyrogen with the opioid analgesic alfentanil in an animal model. Alfentanil was infused over 10 min into 17 conscious rabbits and over 120 min in another 12 animals. Some of them had been randomized to pretreatment with Escherichia coli endotoxin. Arterial plasma concentrations of alfentanil were determined repeatedly, and arterial blood gas values were recorded. Endotoxin antagonized the respiratory depressant effect of the 10-min infusion of alfentanil by increasing drug distribution clearance during the infusion. In addition, endotoxin raised the total volume of distribution of alfentanil from 0.70 to 1.4 L/kg. Plasma protein binding and elimination clearance were not affected. The increase in volume of distribution and the lack of effect of endotoxin on elimination clearance were confirmed in the 120-min infusion experiments. Apparent concentration-effect relationships for the actions of alfentanil on arterial CO2, O2, and pH were not influenced by the endotoxin. Circulating pyrogens can thus influence the pharmacokinetics and, indirectly, the effects of alfentanil.