Identification of human liver cytochrome P450 isoforms mediating secondary omeprazole metabolism.

Andersson, Tommy; Miners, John O.; Veronese, Maurice E.; Birkett, D. J.

doi:10.1111/j.1365-2125.1994.tb04310.x

Cited by 128 publications

(80 citation statements)

References 22 publications

(29 reference statements)

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“…After standing for 30 min at room temperature, each sample was pre-incubated for 3 min at 37°C with the final concentration of each 5 mM PPI, followed by the same procedure related above. Compared with other in vitro experiments, 6,7,9,12,13) each PPI concentration in microsomal samples was lower (0.4 or 5 mM), and their values were close to or less than the maximum concentration in clinical use, that is, omeprazole: 1.5-3 mM, lansoprazole: 1.2-4 mM and rabeprazole: 1.2 mM.…”

Section: Methodsmentioning

confidence: 99%

Different Contribution of CYP2C19 in the in Vitro Metabolism of Three Proton Pump Inhibitors.

Kita

Sakaeda

Baba

et al. 2003

Biological & Pharmaceutical Bulletin

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Inter-individual variation in the pharmacokinetics and thereby pharmacodynamics of many therapeutic agents are possibly caused by genetic polymorphisms of drug metabolizing enzymes including cytochrome P450 2C9 (CYP2C9), CYP2C19 and CYP2D6. A series of clinical studies on the CYP2C19 genotype and the pharmacokinetics and pharmacodynamics of three proton pump inhibitors (PPIs), omeprazole, lansoprazole and rabeprazole, were conducted to establish the individualized pharmacotherapy based on the CYP2C19 genotyping. [1][2][3][4][5] The subjects were classified into homo extensive metabolizers, hetero extensive metabolizers and poor metabolizers according to the CYP2C19 genotype diagnosed. The findings were summarized as follows: 1) plasma concentrations of omeprazole and lansoprazole after single oral administration were defined by the CYP2C19 genotype, whereas rabeprazole was not, 2) the CYP2C19 genotype-dependency of lansoprazole was weaker than omeprazole, and 3) hetero extensive metabolizers could be included with homo extensive metabolizers to be extensive metabolizers. There were several in vitro studies reporting that CYP2C19 and CYP3A4 were responsible for the metabolism of 3 PPIs, however, little information is available for their relative contributions on total metabolism, 6-10) that would be adequate to explain that the CYP2C19 genotypedependent pharmacokinetics was more marked for omeprazole than the other two. Herein, to validate further the difference among 3 PPIs in CYP2C19 genotype-dependency on the phenotype, a comparative in vitro study on the metabolism of 3 PPIs was conducted using human liver microsomes and newly developed anti-human CYP antibodies. MATERIALS AND METHODS MaterialsOmeprazole and its two primary metabolites, 5-hydroxyomeprazole and omeprazole sulfone, were obtained from AstraZeneca Ltd. (Osaka, Japan). Lansoprazole and its two primary metabolites, 5-hydroxylansoprazole and lansoprazole sulfone, were obtained from Takeda Pharmaceutical Co. (Osaka, Japan). The internal standard for rabeprazole (IS735), rabeprazole and its two primary metabolites, thioether rabeprazole and rabeprazole sulfone, were obtained from Eisai Co. (Tokyo, Japan). All other chemicals were of reagent grade and obtained commercially. Six lots of human liver microsomes (Table 1) were purchased from KAC Co. Ltd. (Kyoto, Japan). Anti-human CYP antibodies raised against bacterial expressed recombinant human CYP2C19 and CYP3A4 (referred to as anti-CYP2C19 and anti-CYP3A4 antibodies, respectively) were prepared in rabbits according to the method of Kaminsky et al. 11) Cross reactivity of antibodies raised against CYP2C19 and 3A4 were checked by means of ELISA. Anti-CYP2C19 antibody recognized CYP2C19 and slightly cross reacted with CYP2C9, but did not react with CYP1A2, 2D6, 2E1 and 3A4. Under the condition employed in the present study, cross reaction between CYP2C9 and anti-CYP2C19 antibody is minimized. On the other hand, anti-CYP3A4 antibody recognized CYP3A4, but did not react with CYP1A2, 2C9, 2C19, 2D6 and 2E...

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Section: Methodsmentioning

confidence: 99%

Different Contribution of CYP2C19 in the in Vitro Metabolism of Three Proton Pump Inhibitors.

Kita

Sakaeda

Baba

et al. 2003

Biological & Pharmaceutical Bulletin

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“…However, 5-hydroxyomeprazole itself is also metabolized to hydroxysulfon by CYP3A4. [22] Furthermore, the measurement of 5-hydroxyomeprazole is not validated in combination with the other drugs used in our cocktail approach. The addition of 5-hydroxyomeprazole to our analysis would therefore not make omeprazole a better probe for CYP2C19.…”

Section: Discussionmentioning

confidence: 99%

A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects

Achterbergh

Lammers

Nierop

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Objectives: Knowledge of factors contributing to variation in drug metabolism is of vital importance to optimize drug treatment. This study assesses the effects of a short-term hypercaloric high fat diet on metabolism of five oral drugs, which are each specific for a single P450 isoform: midazolam (CYP3A4), omeprazole (CYP2C19), metoprolol (CYP2D6), S-warfarin (CYP2C9) and caffeine (CYP1A2). Methods: In 9 healthy volunteers, pharmacokinetics of the five drugs were assessed after an overnight fast at two separate occasions: after a regular diet and after 3 days of a hypercaloric high fat diet (i.e. regular diet supplemented with 500 mL cream [1715 kcal, 35% fat]). Pharmacokinetic parameters (mean [SEM]) were estimated by non-compartmental analysis. Results: The high fat diet increased exposure to midazolam by 19% from 24.7 (2.6) to 29.5 (3.6) ng ml1h-1 (p=0.04) and exposure to omeprazole by 31% from 726 (104) to 951 (168) ng ml-1h-1 (p=0.05). Exposure to metoprolol, caffeine and S-warfarin was not affected by the high fat diet. Conclusion: A short-term hypercaloric high fat diet increases exposure to midazolam and omeprazole, possibly reflecting modulation of CYP3A4 and CYP2C19.ARTICLE HISTORY

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“…In case of omeprazole N-oxygenation by CYP3A, it was not possible to determine specific activities or V max but the authors estimated an apparent K m of 600 lM [31]. All these K m values are higher or at best in the same range as the K m of AaP for PY (69 lM), however, the specific activity of AaP is about 100-fold higher.…”

Section: Kinetic Data Of Py N-oxidationmentioning

confidence: 99%

Pyridine as novel substrate for regioselective oxygenation with aromatic peroxygenase from Agrocybe aegerita

et al. 2008

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Agrocybe aegerita peroxidase (AaP) is a versatile extracellular biocatalyst that can oxygenate aromatic compounds. Here, we report on the selective oxidation of pyridine (PY) yielding pyridine N-oxide as sole product. Using H 2 18 O 2 as co-substrate, the origin of oxygen was confirmed to be the peroxide. Therefore, AaP can be regarded as a true peroxygenase transferring one oxygen atom from peroxide to the substrate. To our best knowledge, there are only two types of enzymes oxidizing PY at the nitrogen: bacterial methane monooxygenase and a few P450 monooxygenases. AaP is the first extracellular enzyme and the first peroxidase that catalyzes this reaction, and it converted also substituted PYs into the corresponding N-oxides.

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Identification of human liver cytochrome P450 isoforms mediating secondary omeprazole metabolism.

Cited by 128 publications

References 22 publications

Different Contribution of CYP2C19 in the in Vitro Metabolism of Three Proton Pump Inhibitors.

Different Contribution of CYP2C19 in the in Vitro Metabolism of Three Proton Pump Inhibitors.

A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects

Pyridine as novel substrate for regioselective oxygenation with aromatic peroxygenase from Agrocybe aegerita

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