Intestinal 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.
An open randomized two-way crossover study was performed. Ten patients (3 females, 7 males) with liver cirrhosis based on biopsy or clinical criteria participated. Six patients had a Child-Pugh score of A, one B and three C. Tap water (200 ml) or grapefruit juice were consumed 60 and 15 min before midazolam (15 mg) was administered orally. Plasma samples were analysed for midazolam and alpha-hydroxymidazolam.
Grapefruit juice increased the AUC of midazolam by 106% (16, 197%) (mean (95% confidence interval)) and the AUC of the metabolite alpha-hydroxymidazolam decreased to 25% (12, 37%) (P<0.05 for both). The ratio of the AUCs of the metabolite alpha-hydroxymidazolam to midazolam decreased from 0.77 (0.46, 1.07) to 0.11 (0.05, 0.19) (P<0.05). t(1/2) remained unaltered for both drug and metabolite. Midazolam C(max), t(max), and alpha-hydroxymidazolam t(max) increased, but these changes were not statistically significant, whereas C(max) of the metabolite decreased to 30% (14, 47%) (P<0.05).
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.
AuthorsVibeke Andersen, Natalie Pedersen, Niels-Erik Larsen, Jesper Sonne, Steen Larsen
JournalBritish journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 54 Issue 2 Pg. 120-4 (Aug 2002) ISSN: 0306-5251 [Print] England
PMID12207630 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Hypnotics and Sedatives
  • 1-hydroxymethylmidazolam
  • Cytochrome P-450 Enzyme System
  • Midazolam
  • Adult
  • Aged
  • Biological Availability
  • Citrus (metabolism)
  • Cross-Over Studies
  • Cytochrome P-450 Enzyme System (metabolism)
  • Female
  • Food-Drug Interactions
  • Humans
  • Hypnotics and Sedatives (blood, metabolism, pharmacokinetics)
  • Intestines (metabolism)
  • Liver Cirrhosis (enzymology)
  • Male
  • Midazolam (analogs & derivatives, blood, metabolism, pharmacokinetics)
  • Middle Aged

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