Clearance of fentanyl, alfentanil, methohexitone, thiopentone and ketaminein relation to estimated hepatic blood flow in several animal species: Application to prediction of clearance in man

We have used estimated hepatic blood flow (Q(hep)) as an aid to evaluate cl earance (CL) values in animals and to predict clearance in man of five anae sthetic agents: fentanyl, alfentanil, methohexitone, thiopentone and ketami ne. The disposition of methohexitone was determined in rats and that of ketamin e 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 clearanc e and unbound clearance (CLu) in man. The results of scaling according to t he three different methods were evaluated in relation to estimated hepatic extraction ratio (CL/Q(hep)) of the drugs. In most animals the clearance of the drugs were comparable with or lower th an estimated Q(hep). However, ketamine showed extensive extrahepatic cleara nce in rabbits. Prediction of clearance in man was successful by at least o ne method for all five drugs, while prediction of CLu generally failed. Est imates of CL/Q(hep) 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 Q(hep) should be used to evaluate clearance da ta in animals, however estimation of hepatic extraction ratios appears to b e of little use for allometric scaling. The use of ketamine as an anaesthet ic agent in rabbits is questionable, while the use of fentanyl in pigs, met hohexitone in rats and ketamine in rats and pigs is well supported by the p harmacokinetic data.