Rat liver slices and diazepam metabolism: In vitro interactions with volatile anaesthetic drugs and albumin

Summary: The influence of the volatile anaesthetic agents enflurane, isoflurane, halothane and the halothane metabolite trifluoroacetic acid was studied on the hepatic elimination of diazepam, by incubating precision-cut slices of rat liver in a closed system. The impact of anaesthetic-induced action on enzyme activity and diazepam binding to human serum albumin (HSA) was assessed in protein free and protein containing buffers, respectively. Human serum albumin reduced the elimination of diazepam by 12 and 50% at concentrations of 1 and 10 mg ml^-1, respectively. In the absence of albumin, halothane 1 mmol litre^-1 reduced the elimination of diazepam by 13%, whereas enflurane at 1.5 mmol litre^-1 caused a reduction of 8%. No effect was seen from isoflurane 1 mmol litre^-1 and trifluoroacetic acid 4 mmol litre^-1. In the presence of the highest concentration of albumin, however, an increased elimination of diazepam of 24% resulted from exposure to enflurane and trifluoroacetic acid, while no statistically significant changes were seen for isoflurane and halothane. The present work supports the view that volatile anaesthetic agents may cause pharmacokinetic drug interactions by interference with both enzyme activity and drug protein binding.