Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans*

Furuta, Takahisa; Ohashi, Kyoichi; Kobayashi, Kaoru; Iida, Ikuo; Yoshida, Hideo; Shirai, Naohito; Takashima, Misako; Kosuge, Kazuhiro; Hanai, Hiroyuki; Chiba, Kazuhiro; Ishizaki, Takashi; Kaneko, Eizō

doi:10.1016/s0009-9236(99)70034-2

Cited by 116 publications

(87 citation statements)

References 33 publications

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“…It has been confirmed that clarithromycin reduces the elimination of drugs metabolized by CYP3A, such as midazolam (Gorski et al, 1998), omeprazole (Furuta et al, 1999), and cisapride (van Haarst AD et al, 1998;Piquette, 1999) in vivo. Because olopatadine, like imipramine, contains an alkylamino moiety there was a possibility that it also might inhibit P450 activities via the formation of MIC.…”

Section: Fig 2 Mass Spectra Of M1 (A) M3 (B) and Olopatadine (C)mentioning

confidence: 92%

Effects of Olopatadine, a New Antiallergic Agent, on Human Liver Microsomal Cytochrome P450 Activities

Kajita

Inano²,

Fuse³

et al. 2002

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Olopatadine, a new histamine H 1 receptor-selective antagonist, is a tricyclic drug containing an alkylamino moiety. Some compounds containing a similar alkylamino group form a cytochrome P450 (P450) -iron (II)-nitrosoalkane metabolite complex [metabolic intermediate complex (MIC)], thereby causing quasi-irreversible inhibition of the P450. There was concern that olopatadine might also form MICs, therefore, the present investigation was undertaken to explore this possibility. We identified the enzymes catalyzing olopatadine metabolism and investigated the effect of olopatadine on human P450 activities. During incubation with human liver microsomes in the presence of a NADPH-generating system, olopatadine was metabolized to two metabolites, M1 (N-monodemethylolopatadine) and M3 (olopatadine N-oxide) at rates of 0.330 and 2.50 pmol/min/mg protein, respectively. Troleandomycin and ketoconazole, which are both selective inhibitors of CYP3A, significantly reduced M1 formation but specific inhibitors of other P450 isozymes did not decrease M1 formation. Incubation of olopatadine with cDNA-expressed human P450 isozymes confirmed that M1 formation was almost exclusively catalyzed by CYP3A4. The formation of M3 was enhanced by N-octylamine and was inhibited by thiourea. High specific activity of M3 formation was exhibited by cDNA-expressed flavin-containing monooxygenase (FMO)1 and FMO3. Olopatadine did not inhibit P450 activities when it was simultaneously incubated with substrates for different P450 isozymes. Also, P450 activities in human liver microsomes were unaffected by pretreatment with olopatadine or M1. Furthermore, spectral analysis revealed that neither olopatadine nor M1 formed an MIC. Therefore, it is unlikely that olopatadine will cause drugdrug interactions involving P450 isozymes.Olopatadine, (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, is a new histamine H 1 receptorselective antagonist (Ohshima et al., 1992) that is used in the clinic for the treatment of allergic rhinitis, chronic urticaria, eczema, dermatitis, and conjunctivitis. After oral administration of [ 14 C]olopatadine to rats and dogs, the main metabolic pathways were 1) N-demethylation to M1 and M2, the N-monodemethyl and N-didemethyl analogs, respectively; 2) hydroxylation of dihydrodibenz [b,e]oxepin ring (M5); and 3) sulfoconjugation of M5 (M4) and N-oxidation (M3) (Ohishi et al., 1995; Fig. 1). After oral administration of olopatadine to human subjects, the metabolites detected in plasma were M1 and M3, but the areas under the plasma concentration-time curve of both M1 and M3 were lower than that of unchanged drug (Fujita et al., 1999). The main elimination pathway of olopatadine in human subjects and animals was via excretion of unchanged drug in urine. Urinary metabolites were mainly M1 and M3, but the amounts of these metabolites were much lower than that of unchanged drug in rat, dog (Ohishi et al., 1995), and human (Tsuno...

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Section: Fig 2 Mass Spectra Of M1 (A) M3 (B) and Olopatadine (C)mentioning

confidence: 92%

Effects of Olopatadine, a New Antiallergic Agent, on Human Liver Microsomal Cytochrome P450 Activities

Kajita

Inano²,

Fuse³

et al. 2002

Drug Metab Dispos

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“…1) Recently, Furuta et al 15) empirically reported that an extra-high dose of omeprazole (40 mgϫ3/d) achieved eradication in an extensive metabolizer.…”

Section: 3)mentioning

confidence: 99%

“…11,12) In anti-H. pylori therapy using omeprazole (20 mgϫ2/d for 1 week), amoxicillin (500 mgϫ4/d for 1 week), and clarithromycin (200 mgϫ4/d for 1 week), patients who were poor metabolizers all achieved eradication, while 17% of extensive metabolizers failed. 13,14) Several studies have shown that this therapeutic inefficacy might be overcome by high-dose omeprazole.1) Recently, Furuta et al 15) empirically reported that an extra-high dose of omeprazole (40 mgϫ3/d) achieved eradication in an extensive metabolizer.In the present study, a single oral dose of omeprazole 20, 40, and 80 mg was administered to 7 healthy Japanese subjects with the CYP2C19 genotype. The recommended dose of omeprazole for extensive metabolizers was estimated in anti-H. pylori therapy based on pharmacokinetic considerations.…”

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confidence: 99%

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Optimal Dose of Omeprazole for CYP2C19 Extensive Metabolizers in Anti-Helicobacter pylori Therapy: Pharmacokinetic Considerations.

Kita

Sakaeda

Aoyama

et al. 2002

Biological & Pharmaceutical Bulletin

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Proton pump inhibitors are occasionally used in therapy for eradicating Helicobacter pylori in the combination with antimicrobials, [1][2][3][4][5] for the prevention of gastric and duodenal ulcer diseases.1,2) Triple therapy using omeprazole, amoxicillin, and clarithromycin is now recommended for anti-H. pylori therapy because of its high eradication rate (greater than 90%), [3][4][5] although problems with this therapy have arisen including the resistance of H. pylori to clarithromycin by failure. 2,3)Omeprazole is extensively metabolized into the primary metabolites of 5Ј-hydroxyomeprazole and omeprazole sulfone (Fig. 1). Formation of the 5Ј-hydroxyomeprazole is mediated mainly by cytochrome P450 2C19 (CYP2C19) with only a minor contribution of CYP3A4 and others. 6) CYP2C19, often referred to as S-mephenytoin 4Ј-hydroxylase, shows genetically determined polymorphism of enzyme activity with bimodal distributions. 7) In 1994, two mutant alleles, CYP2C19*2 and CYP2C19*3, were found in addition to a wild-type allele, CYP2C19*1, and six different genotypic patterns were theoretically defined. [8][9][10] In our previous studies, the pharmacokinetics of omeprazole and gastric pH after omeprazole administration in healthy subjects were also defined by bimodal distribution, and two groups were genetically assigned based on CYP2C19 genotypes: extensive metabolizers and poor metabolizers. 11,12) In anti-H. pylori therapy using omeprazole (20 mgϫ2/d for 1 week), amoxicillin (500 mgϫ4/d for 1 week), and clarithromycin (200 mgϫ4/d for 1 week), patients who were poor metabolizers all achieved eradication, while 17% of extensive metabolizers failed. 13,14) Several studies have shown that this therapeutic inefficacy might be overcome by high-dose omeprazole.1) Recently, Furuta et al. 15) empirically reported that an extra-high dose of omeprazole (40 mgϫ3/d) achieved eradication in an extensive metabolizer.In the present study, a single oral dose of omeprazole 20, 40, and 80 mg was administered to 7 healthy Japanese subjects with the CYP2C19 genotype. The recommended dose of omeprazole for extensive metabolizers was estimated in anti-H. pylori therapy based on pharmacokinetic considerations. MATERIALS AND METHODS ChemicalsOmeprazole and its two metabolites, 5Ј-hydroxyomeprazole and omeprazole sulfone, were obtained In anti-Helicobacter pylori therapy using omeprazole and antimicrobials, the efficacy can be related to the CYP2C19 genotype groups; the eradication rates were 83% in extensive metabolizers and 100% in poor metabolizers. The present study was undertaken to help predict the optimal dosage of omeprazole for extensive metabolizers in this therapy. Seven healthy Japanese subjects, classified based on the CYP2C19 genotype into extensive metabolizers (n‫)4؍‬ and poor metabolizers (n‫,)3؍‬ participated in this study. Each subject received a single oral dose of omeprazole 20, 40, and 80 mg, with at least a 1-week washout period between each dose. Plasma concentrations of omeprazole and its two metabolites were monitored for...

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“…The increasing use of thalidomide raises the possibility of metabolic interactions with other prescription medications. 13) Clinically important interactions between thalidomide and coadministered therapeutics may affect the activation or detoxification of thalidomide and other drugs giving rise to attenuation or amplification of biological effects and/or toxicities. While metabolic studies have been performed in animals, 6) to date there have been only a few human studies.…”

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confidence: 99%

Influence of Cytochrome P450 2C19 Gene Variations on Pharmacokinetic Parameters of Thalidomide in Japanese Patients

Matsuzawa

Nakamura

Matsuda

et al. 2012

Biological & Pharmaceutical Bulletin

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Purpose: Cytochrome P450 (CYP)2C19 polymorphisms may partly explain the variability of thalidomide concentration and adverse drug effects by altering its metabolism. To compare the genetic and clinical factors responsible for the adverse effects and efficacy of thalidomide treatment, we investigated CYP2C19 genetic polymorphisms in Japanese subjects. Materials and Methods: Variations in the CYP2C19 gene in 6 patients treated with thalidomide were analyzed. The dosage of thalidomide, concentrations of (R)-and (S)-thalidomide in whole blood, and clinical laboratory test results were used as pharmacokinetic and pharmacodynamic indices. Using genomic DNA, CYP2C19*2 and *3 allele frequencies were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. Results: The frequencies of CYP2C19 PM and hetero EM (hetEM) genotypes in Japanese patients taking thalidomide were 2 (33.3%) and 4 (66.7%), respectively. The areas under the curve (AUC) of (R)-thalidomide were 3.42 and 5.33 μg·h/L, and those of (S)-thalidomide were 1.64 and 2.46 μg·h/L for hetEM and PM, respectively. Conclusions: This study provided new insights regarding the contribution of CYP2C19 gene variations to adverse responses to thalidomide. Genotyping of CYP2C19*2 and *3 can be considerably simplified by using KOD FX as a polymerase for prediction of adverse effects to thalidomide by the PCR-RFLP method. CYP2C19 PM patients tend to have high serum thalidomide concentrations.

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Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans*

Abstract: Clarithromycin inhibits the metabolism of omeprazole. Drug interaction between clarithromycin and omeprazole may underlie high eradication rates achieved by triple therapy with omeprazole, amoxicillin, and clarithromycin.

Cited by 116 publications

References 33 publications

Effects of Olopatadine, a New Antiallergic Agent, on Human Liver Microsomal Cytochrome P450 Activities

Effects of Olopatadine, a New Antiallergic Agent, on Human Liver Microsomal Cytochrome P450 Activities

Optimal Dose of Omeprazole for CYP2C19 Extensive Metabolizers in Anti-Helicobacter pylori Therapy: Pharmacokinetic Considerations.

Influence of Cytochrome P450 2C19 Gene Variations on Pharmacokinetic Parameters of Thalidomide in Japanese Patients

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