British journal of clinical pharmacology
-
Br J Clin Pharmacol · Aug 2002
Randomized Controlled Trial Clinical TrialIntestinal first pass metabolism of midazolam in liver cirrhosis --effect of grapefruit juice.
Grapefruit juice inhibits CYP3A4 in the intestinal wall leading to a reduced intestinal first pass metabolism and thereby an increased oral bioavailability of certain drugs. For example, it has been shown that the oral bioavailability of midazolam, a CYP3A4 substrate, increased by 52% in healthy subjects after ingestion of grapefruit juice. However, this interaction has not been studied in patients with impaired liver function. Accordingly, the effect of grapefruit juice on the AUC of midazolam and the metabolite alpha-hydroxymidazolam was studied in patients with cirrhosis of the liver. ⋯ A marked interaction between oral midazolam and grapefruit juice was found and the data are consistent with a reduced first-pass metabolism of midazolam. This is likely to occur at the intestinal wall inhibition of CYP3A4 activity by grapefruit juice. These results indicate that patients with liver cirrhosis are more dependent on the intestine for metabolism of CYP3A4 substrates than subjects with normal liver function.