Metabolic and analytical interactions of grapefruit juice and 1,2-benzopyrone (coumarin) in man.

OBJECTIVE

Grapefruit juice is known to inhibit mammalian cytochrome P450 isozymes such as CYP3A4. The aim of this study was to investigate the influence of the juice on the fate of coumarin (1,2-benzopyrone) metabolized by CYP2A6 in man. Its potentially inhibitory effect was examined when low and high amounts of grapefruit juice were taken.

METHODS

In crossover studies, doses of 10 mg coumarin (Venalot) were given orally to an healthy male volunteer. The drug was taken either with water or with grapefruit juice, at different volumes (300 ml or 4 x 250 ml at intervals of 30 min). Urine samples were collected up to 24 h after dosing. After in vitro hydrolysis they were analysed fluorimetrically for umbelliferone, the metabolite of coumarin, and cumulative excretion curves were established. HPLC and TLC served to identify fluorescent metabolites from the juice.

RESULTS

If coumarin is given in water its excretion is complete after 6 h and 70% of the dose is recovered. Grapefruit juice (300 ml) given simultaneously slightly retards the appearance of the fluorescent metabolite in the urine within the first few hours. The recovery of coumarin remains unaffected. One litre of juice enhances the delay and increases the recovery of coumarin to nearly 100%. Respective controls with grapefruit juice alone lead to remarkable excretions of a fluorescent material identified as conjugated scopoletin, which strongly interferes with the analysis of the coumarin experiment. The precursor of scopoletin is widely present at different concentrations in commercially available grapefruit juices. However, the autoinhibition of the juice is correlated neither to the concentration of naringin nor to that of scopoletin.

CONCLUSION

Only grapefruit juice given at high doses (1 L) retards the appearance of the main metabolite of coumarin administered orally but increases its recovery. Due to scopoletin formed from the grapefruit juice, experiments especially with coumarin are strongly affected.