The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: The role of gut CYP3A and P-glycoprotein

• Published in: Life sciences (1973) Vol. 71; no. 10; pp. 1149 - 1160
• Main Authors: Di Marco, Marika Pasternyk, Edwards, David J, Wainer, Irving W, Ducharme, Murray P
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 26-07-2002
• Subjects: Adolescent; Adult; Antitussive Agents - pharmacokinetics; Aryl Hydrocarbon Hydroxylases; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Beverages - adverse effects; Biological Availability; Biotransformation; Citrus; CYP2D6; CYP3A; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Dealkylation; Dextromethorphan; Dextromethorphan - pharmacokinetics; Digestive System - enzymology; Digestive System - metabolism; Female; Food-Drug Interactions; Grapefruit juice (GJ); Humans; Male; Membrane Proteins - metabolism; Oxidoreductases, N-Demethylating - antagonists & inhibitors; Oxidoreductases, N-Demethylating - metabolism; P-glycoprotein (P-gp); Phenotype; Reproducibility of Results; Seville orange juice (SOJ); CYP3A; P-glycoprotein (P-gp); Dextromethorphan; Seville orange juice (SOJ); CYP2D6; Grapefruit juice (GJ)
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/S0024-3205(02)01799-X

The objective of this study was to determine the effects of grapefruit juice and seville orange juice on dextromethorphan (DM) pharmacokinetics. Eleven healthy volunteers were studied over a 3-week period consisting of 5 study days each separated by a three-day washout. All subjects refrained from drinking caffeine containing beverages (coffee, soda, etc.) 8 h before orally taking DM (30 mg) with 200 ml water, 200 ml grapefruit juice, 200 ml water, 200 ml seville orange juice, and 200 ml water on Study Days 1 to 5. Aliquots of urine samples were assayed and analysed for DM, and the DM metabolites dextrorphan, 3-methoxymorphinan and 3-hydroxymorphinan using a validated HPLC method employing a phenyl column and a fluorescence detection. Results suggests that DM could provide some useful information on P-glycoprotein or related membrane efflux protein activity in the human gastro-intestinal tract. Bioavailability (F) of DM increased significantly with grapefruit and seville orange juice, but only returned to half the baseline value after three days of washout. This confirms that grapefruit and seville orange juice are long-lasting and perhaps irreversible inhibitors of gut CYP3A/P-glycoprotein. Grapefruit and seville orange juice appeared to have the same overall effect on DM pharmacokinetics. In addition, this paper presents a novel method of phenotyping for CYP2D6, CYP3A and P-glycoprotein using DM as a probe.