Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism

Andersson, Tommy; Miners, John O.; Veronese, Maurice E.; Tassaneeyakul, Wichittra; Tassaneeyakul, Wongwiwat; Meyer, Urs; Birkett, Donald

doi:10.1111/j.1365-2125.1993.tb00410.x

Cited by 191 publications

(127 citation statements)

References 24 publications

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“…The major metabolites of omeprazole detected in vivo in human plasma are 5-hydroxyomeprazole formed by CYP2C19 and omeprazole sulphone formed by CYP3A4 [5,6]. The metabolic disposition of omeprazole correlates well with the rate of S-mephenytoin hydroxylation [7] and those two drugs are the most commonly used probes of CYP2C19.…”

Section: Discussionmentioning

confidence: 99%

CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

Ramsjö

Aklillu

Bohman

et al. 2010

Eur J Clin Pharmacol

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Objectives To compare CYP2C19 enzyme activity between Swedes and Koreans controlling for the effect of CYP2C19 genotype, sex, oral contraceptive use and smoking habit.Methods CYP2C19 activity was determined in 185 healthy Swedish and 150 Korean subjects as omeprazole/5-hydroxyomeprazole ratio (metabolic ratio; MR) using high-performance liquid chromatography. Genotyping was performed by PCR using Taqman assay.Results As expected, a higher incidence of poor metabolizers (PM) was found in Koreans (14%) compared to Swedes (3.8%) and the frequency of the CYP2C19*17 allele was very low in Koreans 0.3%. Among subjects homozygous for CYP2C19*1, Koreans displayed significantly lower CYP2C19 enzyme activity than Swedes (p<0.000001). Interestingly in Koreans a pronounced gender difference was apparent: females (n=24) had significantly lower MR than males (N=30) (p<0.0001) but such a gender difference was not seen among Swedes. Swedish OC users had a higher MR than non-users (p<0.00001), whereas OC was only used by one Korean. No effect of smoking was observed. ConclusionsWe find specific gender dependent effects of CYP2C19 activity in Koreans but not in Swedes. Controlling for the effect of genotype and sex, Koreans display lower CYP2C19 activity than Swedes. The genetic, epigenetic or environmental basis for this difference remains to be identified.

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Section: Discussionmentioning

confidence: 99%

CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

Ramsjö

Aklillu

Bohman

et al. 2010

Eur J Clin Pharmacol

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“…The probe drugs and doses in this cocktail were chosen to be selective for individual CYP isoforms, with the expectation of no or minimal interference between probes [5,[9][10][11][12][13][14][15][16][17]. However, loss of selectivity of a probe drug may be possible if the CYP isoform responsible for the metabolism of the probe drug is inhibited by the test compound and probe concentrations are elevated.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic assessment of a five‐probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A

Turpault

Brian

Horn

et al. 2009

Brit J Clinical Pharma

132

127

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Numerous cocktails using concurrent administration of several cytochrome P450 (CYP) isoform‐selective probe drugs have been reported to investigate drug–drug interactions in vivo.• This approach has several advantages: characterize the inhibitory or induction potential of compounds in development toward the CYP enzymes identified in vitro in an in vivo situation, assess several enzymes in the same trial, and have complete in vivo information about potential CYP‐based drug interactions. WHAT THIS STUDY ADDS • This study describes a new cocktail containing five probe drugs that has never been published.• This cocktail can be used to test the effects of a new chemical entity on multiple CYP isoforms in a single clinical study: CYP1A2 (caffeine), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A (midazolam) and was designed to overcome potential liabilities of other reported cocktails.AIMS To assess the pharmacokinetics (PK) of selective substrates of CYP1A2 (caffeine), CYP2C9 (S‐warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol) and CYP3A (midazolam) when administered orally and concurrently as a cocktail relative to the drugs administered alone.METHODS This was an open‐label, single‐dose, randomized, six‐treatment six‐period six‐sequence William's design study with a wash‐out of 7 or 14 days. Thirty healthy male subjects received 100 mg caffeine, 100 mg metoprolol, 0.03 mg kg−1 midazolam, 20 mg omeprazole and 10 mg warfarin individually and in combination (cocktail). Poor metabolizers of CYP2C9, 2C19 and 2D6 were excluded. Plasma samples were obtained up to 48 h for caffeine, metoprolol and omeprazole, 12 h for midazolam, 312 h for warfarin and the cocktail. Three different validated liquid chromatography tandem mass spectrometry methods were used. Noncompartmental PK parameters were calculated. Log‐transformed Cmax, AUClast and AUC for each analyte were analysed with a linear mixed effects model with fixed term for treatment, sequence and period, and random term for subject within sequence. Point estimates (90% CI) for treatment ratios (individual/cocktail) were computed for each analyte Cmax, AUClast and AUC.RESULTS There was no PK interaction between the probe drugs when administered in combination as a cocktail, relative to the probes administered alone, as the 90% CI of the PK parameters was within the prespecified bioequivalence limits of 0.80, 1.25.CONCLUSION The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug–drug interactions in vivo.

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“…Omeprazole has recently been shown to be metabolized by the cytochrome P450 enzymes 3A4 (CYP3A4) and 2C19 (CYP2C19) [3]. Because of the effects of cimetidine on drug metabolism [4], there has been considerable interest in the effects of omeprazole on drug metabolism.…”

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confidence: 99%

Omeprazole does not affect measured CYP3A4 activity using the erythromycin breath test [letter]

Tateishi¹,

Graham²,

Krivoruk³

et al. 1995

Brit J Clinical Pharma

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Omeprazole is a potent inhibitor of H+-ATPase in the gastric parietal cell [1], and is widely used for the treatment of peptic ulcer disease and reflux oesophagitis [2]. Omeprazole has recently been shown to be metabolized by the cytochrome P450 enzymes 3A4 (CYP3A4) and 2C19 (CYP2C19) [3]. Because of the effects of cimetidine on drug metabolism [4], there has been considerable interest in the effects of omeprazole on drug metabolism. Omeprazole has been shown to inhibit the metabolism of a number of drugs including phenytoin, warfarin, and diazepam [5][6][7]. All of these drugs are substrates of CYP2C19 thus suggesting that inhibition of CYP2C19 is produced by omeprazole. A much larger number of drugs are metabolized by CYP3A4 which is the major cytochrome P450 present in human liver. Thus the effects of omeprazole on CYP3A4 activity has considerable importance. Although no single probe has developed universal acceptance as a measure of CYP3A4 activity in vivo, the erythromycin breath test has been the most widely used in vivo index of CYP3A4 activity and we have previously shown that it is inhibited by the CYP3A4 inhibitor ketoconazole [16]. This test involves the intravenous administration of 14C labelled methylerythromycin and the collection of 14Co2 exhaled in breath [8].The purpose of the present study was to determine whether omeprazole, in addition to being a substrate of CYP3A4 also inhibits its activity as measured by the erythromycin breath test.After obtaining the approval of the Vanderbilt Committee for the Protection of Human Subjects, 12 healthy male volunteers aged 20-30 years were recruited into the study and gave written informed consent. The study was a placebo controlled, singleblind crossover design in two parts, each part of similar design. First each volunteer took one placebo capsule (identical to omeprazole 20 mg) twice daily for 7 days. After an overnight fast, the erythromycin breath test was performed on the morning of day seven and then the subjects crossed over to omeprazole. The tests were separated by at least 1 week. For the period of the study the subjects abstained from drinking alcohol and grapefruit juice. The erythromycin breath test was performed as previously The excretion of 14Co2 in the first hour accounted for 3.6 ± 0.6 (s.d.)% of the administered dose following placebo and was similar (3.6 ± 1.1%) after 20 mg omeprazole twice a day for 7 days ( Figure 1).The effects of omeprazole on drug metabolism have been studied in the past and these studies have demonstrated that omeprazole inhibits the metabolism of substrates of CYP2C19. The focus on CYP2C19 substrates preceded the recognition that omeprazole is metabolized not only by CYP2C19, as thought previously, but also by CYP3A4 [10]. Thus it was important to determine whether omeprazole also inhibited the metabolism of CYP3A4 substrates in vivo. CYP3A4 constitutes the dominant portion of cytochrome P450 in human liver and is responsible for the metabolism of a very large range of drugs and endogenous substrates and for th...

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Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism

Cited by 191 publications

References 24 publications

CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

Pharmacokinetic assessment of a five‐probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A

Omeprazole does not affect measured CYP3A4 activity using the erythromycin breath test [letter]

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