SIGNIFICANCE LEVEL
2-More Significant; Documented (more clinical data may
be needed): Assess risk to patient and take action as needed.
MECHANISM OF ACTION
Inhibition of first-pass metabolism via the P-450-3A4
pathway in the intestinal wall. A decrease in P-450 enzyme protein content
due to grapefruit juice has been postulated, leading to irreversible enzyme
inhibition and the need for new enzyme synthesis.
CLINICAL EFFECTS
Serum concentrations of carbamazepine were elevated in
seizure patients ingesting grapefruit juice concomitantly.
PATIENT MANAGEMENT
Avoiding grapefruit juice (g.j.) and choosing a
different citrus fruit may be the most prudent course of action until this
interaction is more completely characterized. Data suggests metabolic
inhibition may last up to 24 hours after g.j. ingestion, therefore staggered
g.j. and drug ingestion may not be sufficient action.
DISCUSSION
In a randomized, cross-over study of ten seizure patients, the
effects of grapefruit juice on the pharmacokinetics of carbamazepine were
determined. All patients were treated with carbamazepine 200 mg three times
daily for 3-4 weeks before the study, and during the entire study period.
Phase 1 included a single dose of carbamazepine ingested with 300 ml of
water (with serum concentration determinations). Phase 2 included one dose
of 200 mg carbamazepine ingested with 300 ml of g.j. on day 1, followed by
another such dose with 300 ml g.j. on day 2 (with serum concentration
determinations). There was a two-day washout period between crossover
treatments. Results indicate a statistically significant increase in serum
concentrations and area under the concentration-time curve (AUC) in the g.j.
arm. Peak concentrations were 6.6 versus 9.2 micrograms per ml, and AUC was
44 versus 62 micrograms-hour per ml in the water and g.j. groups,
respectively.
REFERENCES