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Lack of Significant Effect of Grapefruit Juice on the Pharmacokinetics of Lansoprazole and Its Metabolites in Subjects With Different CYP2C19 Genotypes

From the Department of Pharmacy, Hirosaki University Hospital, Hirosaki, Japan (Dr Uno, Dr Sugawara); the Department of Neuropsychiatry (Dr Yasui-Furukori, Dr Takahata), the Department of Clinical Pharmacology (Dr Yasui-Furukori, Dr Tateishi), and First Department of Internal Medicine (Dr Takahata), Hirosaki University School of Medicine, Hirosaki, Japan.

Address for reprints: Norio Yasui-Furukori, MD, PhD, Department of Neuropsychiatry, Hirosaki University, School of Medicine, Hirosaki 036-8562, Japan.

Key Words: Lansoprazole • CYP2C19 • grapefruit juice

The coadministration of several drugs with grapefruit juice (GFJ) can markedly elevate drug bioavailability probably due to inhibition of CYP3A in the small intestine.^1,2 Some calcium channel antagonists, benzodiazepines, HMG-CoA reductase inhibitors, and cyclosporine are the most affected drugs.^1,2 Bergamottin, naringin, furanocoumarins, and 6',7'-dihydroxybergamottin in grapefruit segments are important for the drug-GFJ interaction.^1,2

Lansoprazole is effective in the treatment of various peptic diseases, including gastric and duodenal ulcer, reflux esophagitis, and Zollinger-Ellison syndrome.³ Several in vitro and in vivo studies have shown that sulfoxidation of lansoprazole is catalyzed by CYP3A,^4,5 while its hydroxylation is catalyzed by CYP2C19.^5,6 To date, there is no published information indicating detailed pharmacokinetic GFJ-lansoprazole interaction in humans. This study was therefore designed to determine whether GFJ affects lansoprazole pharmacokinetics and examined the effects of the CYP2C19 genotype status on this interaction.

	METHODS

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Twenty-one Japanese healthy volunteers (12 men and 9 women) who were Helicobacter pylori–negative were enrolled in this study. Their mean age was 25.7 ± 4.7 years, and their mean body weight was 58.3 ± 13.2 kg. The Ethics Committee of Hirosaki University School of Medicine approved this study protocol, and written informed consent had been obtained from each participant before any examinations. The mutated alleles for CYP2C19, CYP2C19*3(*3) and CYP2C19*2(*2) had been identified in our 100 panels using polymerase chain reaction–restriction fragment length polymorphism methods⁷ prior to this study. The CYP2C19 genotype analyses revealed 5 different patterns as follows: *1/*1 in 6, *1/*2 in 3, *1/*3 in 3, *2/*2 in 5, and *2/*3 in 1. These were divided into 3 groups: homozygous extensive metabolizers (hmEMs; *1/*1, n = 7), heterozygous extensive metabolizers (htEMs; *1/*2 and *1/*3, n = 7), and poor metabolizers (PMs; *2/*2 and *2/*3, n = 7).

A randomized, crossover study design in 2 phases was conducted at intervals of at least 2 weeks. All subjects ingested either 200 mL water or 200 mL GFJ at 8:30 AM. Fresh grapefruits imported from Florida were squeezed immediately before intake as juice. Thereafter, they took 60 mg lansoprazole (Takepron, Takeda Pharmaceutical Co, Ltd, Osaka, Japan) at 9:00 AM with 200 mL water (Table I). No other medications were taken during the study periods. No meal was allowed until 4 hours after the dosing (1:00 PM). The use of alcohol, tea, coffee, and cola was forbidden during the test days. Ingestions of GFJ were not allowed at least 1 week before the test day in both phases.

Blood samplings (10 mL each) for determination of lansoprazole and its metabolites lansoprazole sulfone and 5-hydroxylansoprazole were taken into heparinized tubes just before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after the administration of lansoprazole. Plasma was separated immediately and kept at –30°C until analysis.

Plasma concentrations of lansoprazole, lansoprazole sulfone, and 5-hydroxylansoprazole were quantitated using high-performance liquid chromatography method.⁸

The paired t test, Wilcoxon signed-rank test, 1-way analysis of variance followed by Bonferroni's correction, and Fisher exact test were used. A P value of .05 or less was regarded as significant. SPSS 12.0 for Windows (SPSS Japan Inc, Tokyo) was used for these statistical analyses.

	RESULTS

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The mean total area under the curve (AUC) of lansoprazole in the control phase was a little (18%) but significantly (P < .05) higher than that in the GFJ group. There was no difference in the total AUC of 5-hydroxylansoprazole or lansoprazole sulfone. Plasma C_max, t_max, or the elimination half-life of lansoprazole and its metabolites were not different between the 2 phases. The total AUC ratio of lansoprazole sulfone to lansoprazole (sulfoxidation index) was decreased 42% (P < .01) by GFJ, whereas the total AUC ratio of 5-hydroxylansoprazole to lansoprazole (hydroxylation index) did not differ between the 2 phases.

No differences between the CYP2C19 genotypes were found in subject profiles, including age, body weight, and gender. There was a significant difference in total AUC and elimination half-life of lansoprazole, total AUC of lansoprazole sulfone, hydroxylation index, and sulfoxidation index between CYP2C19 genotypes during both phases of the study. There was a significant difference in C_max value of lansoprazole and lansoprazole sulfone in the GFJ-treated group, whereas there was a significant difference in the C_max value of 5-hydroxylansoprazole in the control group. GFJ treatment significantly increased total AUC of lansoprazole in PMs (26 661 ± 7407 vs 34 487 ± 10 850 ng•h/mL, P < .05), and the total AUC ratio of lansoprazole sulfone/lansoprazole was significantly decreased in hmEMs (0.07 ± 0.05 vs 0.04 ± 0.05, P < .05). No differences in other pharmacokinetic parameters were found between control and GFJ phases (Table II, Figure 1).

View larger version (13K): [in this window] [in a new window]   Figure 1. Plasma concentrations (mean ± SE) of lansoprazole after ingestion of either water (open circles) or grapefruit juice (solid circles) and administration of 60 mg lansoprazole in CYP2C19 homozygous extensive metabolizers (EM; n = 7), heterozygous extensive metabolizers (n = 7) and poor metabolizers (PM; n = 7).

	DISCUSSION

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The result of this study showed that GFJ treatment increased total AUC of lansoprazole and decreased sulfoxidation index, suggesting GFJ partially inhibits the formation of lansoprazole sulfone catalyzed by CYP3A4. This finding is in accordance with a previous study of omeprazole-GFJ interaction.⁹ In addition, elimination half-life of lansoprazole was not altered by GFJ treatment. These findings suggest that some components in GFJ affect human intestinal major CYP3A4, resulting from the alternation of lansoprazole absorption but not systemic metabolism.

The magnitude of the GFJ interaction depends on the bioavailability of the drug because GFJ is regarded as a CYP3A inhibitor in only the small intestine but not in the liver. Taking 80% to 90% of lansoprazole bioavailability into consideration,¹⁰ this small effect of GFJ on lansoprazole absorption may not be surprising.

The present study showed significant differences in total AUC of lansoprazole between different CYP2C19 genotypes in the control group. The relative values of the total AUC of lansoprazole in hmEMs, htEMs, and PMs were 1:1.5:4.5. This indicates that the CYP2C19 genotype is the determinant in lansoprazole disposition. Likewise, the relative values of the total AUC of lansoprazole in hmEMs, htEMs, and PMs were 1:1.9:6.4, respectively. These findings suggest that the CYP2C19 genotype still plays an important role in lansoprazole pharmacokinetics even when taking lansoprazole with GFJ instead of water.

In conclusion, the present study indicates GFJ results in AUC increases by inhibiting the formation of lansoprazole sulfone. However, it is unlikely that CYP3A inhibition only in the small intestine has an impact on lansoprazole pharmacokinetics because of relatively higher bioavailability of lansoprazole.

	ACKNOWLEDGEMENTS

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None of the authors hold stocks or have a share in any drug company, and none have received any financial support or are working for a drug company.

	REFERENCES

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6. Yasui-Furukori N, Saito M, Uno T, Takahata T, Sugawara K, Tateishi T. Effects of fluvoxamine on lansoprazole pharmacokinetics in relation to CYP2C19 genotypes. J Clin Pharmacol. 2004;44: 1223-1229.[Abstract/Free Full Text]

7. De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol. 1994;46: 594-598.[Abstract]

8. Uno T, Yasui-Furukori N, Takahata T, Sugawara K, Tateishi T. Determination of lansoprazole and two of its metabolites by liquid-liquid extraction and automated column-switching high-performance liquid chromatography: application to measuring CYP2C19 activity. J Chromatogr B. 2005;816: 309-314.

9. Tassaneeyakul W, Vannaprasaht S, Yamazoe Y. Formation of omeprazole sulfone but not 5-hydroxyomeprazole is inhibited by grapefruit juice. Br J Clin Pharmacol. 2000;49: 139-144.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

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