Extra‐hepatic metabolism of midazolam.

Abstract

Six patients received 10 mg of midazolam intravenously during the anhepatic period of liver transplantation. Arterial blood was sampled during this time and for a similar period following revascularisation. The plasma was analysed using gas chromatography and electron capture detection (GC-ECD) for midazolam a-hydroxymidazolam and ahydroxymidazolam glucuronide. Five of the six patients had small but significant concentrations of metabolites detected during the anhepatic period, demonstrating the presence of extra-hepatic sites of metabolism for this drug. The remaining patient had plasma concentrations of metabolites below the lower limit of detection (2,ug 1-1). This may represent a pharmacogenetic abnormality or a temporary failure of midazolam metabolism secondary to the patients illness affecting the extra-hepatic sites of metabolism.

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

“…The findings that the intestinal extraction of midazolam was on average less than 10% in anhepatic liver transplant patients (173) and that the formation of midazolam's 1 -hydroxy metabolite was limited following intravenous administration in such patients (179) are supportive of this assumption, at least with this CYP3A substrate. Thus, midazolam's hepatic extraction ratio was estimated based on knowledge of liver blood flow, and the contribution of intestinal extraction to the overall first-pass effect following oral administration was determined (180).…”

Prediction of Intestinal First-Pass Drug Metabolism

“…This method exploits the time period during transplant surgery when the patient's diseased liver has been removed and before the new organ has been introduced [9,11,29]. A value of F G is estimated from the difference in the AUC after duodenal administration of drug during this time period (when the contribution of the liver to clearance is absent) with the AUC after the same dose given when the liver is in place (when clearance is both hepatic and intestinal).…”

Criteria for immediate postoperative extubation in adult recipients following living-related liver transplantation with total intravenous anesthesia

“…Moreover, there is a lesser degree of midazolam protein binding in patients with advanced hepatic disease, with a subsequent increase in the free fraction of the drug and enhancement of the pharmacologic effect. However, Trouvin et al 11 demonstrated only slightly impaired disposition in cirrhotic patients, and Park et al 12 described the presence of extrahepatic sites of metabolism for midazolam. In our study, this drug was administered only as co-inductant.…”