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

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.

Clearance of Fentanyl, Alfentanil, Methohexitone, Thiopentone and Ketamine in Relation to Estimated Hepatic Blood Flow in Several Animal Species: Application to Prediction of Clearance in Man

“…Previously, we have used the rabbit as an animal model to study the effects of pyrogen-induced fever on the pharmacokinetics of methohexitone (Redke & Bjo Èrkman 1994) and alfentanil (Bjo Èrkman & Redke 1996). A positive correlation of the clearance of methohexitone with body temperature resembled observations in patients with postoperative fever (Redke et al 1991).…”

“…The pharmacokinetics of ketamine were determined in New Zealand White rabbits, using six control animals (2Á2±2Á6 kg) and seven animals (2Á1±3Á1 kg) pretreated with Escherichia coli endotoxin, as previously described for methohexitone (Redke & Bjo Èrkman 1994) and alfentanil (Bjo Èrkman & Redke 1996). The rate of infusion was 9Á7±11Á4 mg kg À1 h À1 for 2 h and blood sampling was at 5, 10,30,60,90,120,123,128,135,145,160,180,210,240,300 and 360 min after the start of the infusion.…”

“…The bloodaplasma concentration ratios (l) of fentanyl in pigs, methohexitone in rats and man, ketamine and norketamine in rats, rabbits and man, and of thiopentone in rabbits were determined invitro by a procedure previously described by Redke & Bjo Èrkman (1994) and Bjo Èrkman & Redke (1996).…”

Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs—Lessons from Animal Studies

“…Of note, multiple other factors can influence the alfentanil-related respiratory effects. For instance, E. coli endotoxin was shown to antagonize the alfentanil-induced respiratory depressant effects by promoting its distribution (increase in its volume of distribution) when infused over 10 min [ 45 ].…”