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.

Abstract

We have used estimated hepatic blood flow (Qhep) as an aid to evaluate clearance (CL) values in animals and to predict clearance in man of five anaesthetic agents: fentanyl, alfentanil, methohexitone, thiopentone and ketamine. The disposition of methohexitone was determined in rats and that of ketamine in rats, rabbits and pigs. Further data were compiled from the literature and supplemented experimentally as needed. Allometric interspecies scaling, according to three different methods, was used to estimate blood clearance and unbound clearance (CLu) in man. The results of scaling according to the three different methods were evaluated in relation to estimated hepatic extraction ratio (CL/Qhep) of the drugs. In most animals the clearance of the drugs were comparable with or lower than estimated Qhep. However, ketamine showed extensive extrahepatic clearance in rabbits. Prediction of clearance in man was successful by at least one method for all five drugs, while prediction of CLu generally failed. Estimates of CL/Qhep gave no indication as to the choice of the best method. Volume of distribution at steady state could be predicted for alfentanil, thiopentone and ketamine. Comparison of clearance with Qhep should be used to evaluate clearance data in animals, however estimation of hepatic extraction ratios appears to be of little use for allometric scaling. The use of ketamine as an anaesthetic agent in rabbits is questionable, while the use of fentanyl in pigs, methohexitone in rats and ketamine in rats and pigs is well supported by the pharmacokinetic data.