Omeprazole and CYP2C19 polymorphism: effects of long‐term treatment on gastrin, pepsinogen I, and chromogranin A in patients with acid related disorders

Sagar, Mohamed; Stridsberg, Mats; Kjellin, Ann; Mårdh, Sven; Seensalu, R

doi:10.1046/j.1365-2036.2000.00835.x

Cited by 32 publications

(29 citation statements)

References 43 publications

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“…The usual dosages of OM, alone or combined with other agents, range from 10 to 40 mg/day for adults. Approximately 80% of doses of OM seem to be cleared by cytochrome P450 2C19 (CYP2C19), but altered CYP2C19 activity does not seem to increase the risk of adverse effects (16,20). The rates of common adverse events during treatment with OM in general practice have been reported in several publications.…”

Section: Discussionmentioning

confidence: 99%

Effect of short-term treatment with low dosages of the proton-pump inhibitor omeprazole on serum chromogranin A levels in man

Giusti¹,

Sidoti²,

Augeri

et al. 2004

European Journal of Endocrinology

103

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Background: Measurement of chromogranin A (CgA) levels in blood can be used to monitor neuroendocrine tumors (NETs). CgA levels may also be elevated in several other endocrine and non-endocrine diseases. It is well known that drugs affecting acid gastric secretion can increase gastrin. Protonpump inhibitors are extensively used but only a few data have been reported on their effects on CgA secretion. Design: The aim of the study was to evaluate the short-term effect of low dosages of omeprazole (OM) on CgA levels and to sensitize endocrinologists to possible false positive values of CgA in order to prevent expensive diagnostic work-up in searching for NETs. Subjects and methods: Thirty-five female and nine male in-patients (18-81 years) were studied. Mild or severe hypertension in 20 patients needed therapy. Endocrine and metabolic diseases were diagnosed in the majority of patients. CgA levels were evaluated before and during OM therapy (10 mg/day, orally). Results: Without OM therapy, CgA levels were 64^6 mg/l. Elevated baseline CgA levels were found in nine subjects. CgA levels were significantly related to age (P , 0.001), creatinine levels (P ¼ 0.03) and the severity of hypertension (P ¼ 0.002). On short-term OM therapy (n ¼ 42; 18.8^2.4 days; range 5-90 days) a significant (P , 0.001) increase in CgA (145^22 mg/l) from baseline (63^7 mg/l) levels was found. The average net CgA increase on short-term OM therapy was 93^20 mg/l. There was a significant correlation between baseline CgA levels and CgA increase on short-term OM therapy (P ¼ 0.004) but not between the increase in CgA and the duration of the therapy. Conclusions: An increase in CgA levels quickly follows the start of low dosages of OM. This release is more pronounced when the baseline CgA levels are already increased by slight renal insufficiency or severe hypertension. In this common clinical situation an intensive work-up for NETs is not justified before reassessment of CgA after the withdrawal of OM.

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Section: Discussionmentioning

confidence: 99%

Effect of short-term treatment with low dosages of the proton-pump inhibitor omeprazole on serum chromogranin A levels in man

Giusti¹,

Sidoti²,

Augeri

et al. 2004

European Journal of Endocrinology

103

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“…Bertilsson and collaborators have found that changes in gut pH after treatment by e.g. omeprazole are more pronounced in CYP2C19 PMs (Sagar et al 2000). Long-term treatment of proton pump inhibitors leads to a more extensive gastrin release in PMs as compared to EMs (Sagar et al 2000).…”

Section: Cytochromes P450mentioning

confidence: 99%

Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy

Ingelman‐Sundberg

Rodríguez‐Antona

2005

Phil. Trans. R. Soc. B

113

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The majority of phase I-and phase II-dependent drug metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively decreased or enhanced drug metabolism. Several examples exist where subjects carrying certain alleles do not benefit from drug therapy due to ultrarapid metabolism caused by multiple genes or by induction of gene expression or, alternatively, suffer from adverse effects of the drug treatment due to the presence of defective alleles. It is likely that future predictive genotyping for such enzymes might benefit 15-25% of drug treatments, and thereby allow prevention of adverse drug reactions and causalities, and thus improve the health of a significant fraction of the patients. However, it will take time before this will be a reality within the clinic. We describe some important aspects in the field with emphasis on cytochrome P450 and discuss also polymorphic aspects of foetal expression of CYP3A5 and CYP3A7.

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“…We found in 72 patients treated for more than one year with 20 mg omeprazole per day, that heterozygous extensive metabolizers had 3 times higher serum gastrin than extensive metabolizers with two functional CYP2C19 alleles (PΩ 0.0001) (Sagar et al 2000). Also concentrations of pepsinogen I and chromogranin A were significantly different in the two genotypic groups.…”

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confidence: 69%

Dose of Proton Pump Inhibitors and the CYP2C19 Genotype

2004

Basic Clin Pharma Tox

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In the previous issue of this journal Hellström & Vitols (2004) reviewed and compared the properties of the proton pump inhibitors. They and Schaffalitzky de Muchadell (2004) agreed that the proton pump inhibitors are comparable with respect to inhibition of gastric acid secretion. The choice of proton pump inhibitors will primarily depend on the price of the recommended dose.Two years after the first proton pump inhibitor, omeprazole was registered, we demonstrated that this drug is metabolized by the polymorphic cytochrome P450 enzyme CYP2C19 (Andersson et al. 1990). The other proton pump inhibitors have subsequently been shown also to be metabolized by CYP2C19. In a MiniReview in this journal, Klotz et al. (2004) now discuss the importance of this polymorphic enzyme for the dosing of the 5 proton pump inhibitors prescribed today. They nicely review the pharmacodynamic effects of the proton pump inhibitors in the 3 genotypes of CYP2C19. In several studies, especially from Japan (Furuta et al. 2002 and other references in the review by Klotz et al., 2004), a higher cure rate in patients with zero (poor metabolizers) or one (heterozygous extensive metabolizers) compared to extensive metabolizers with two functional CYP2C19 genes. The latter genotype group needs a higher dose of the proton pump inhibitor to compensate for their more rapid drug metabolism. I also agree with Klotz et al (2004) claiming ''initial genotyping for this enzyme and higher dosage in extensive metabolizers is likely to improve the clinical efficacy of proton pump inhibitors''.Initially the proton pump inhibitors were used for short periods in time, a few weeks, but today they are used for long-term treatment especially to treat gastro-oesophageal reflux disease. We found in 72 patients treated for more than one year with 20 mg omeprazole per day, that heterozygous extensive metabolizers had 3 times higher serum gastrin than extensive metabolizers with two functional CYP2C19 alleles (PΩ 0.0001) (Sagar et al. 2000). Also concentrations of pepsinogen I and chromogranin A were significantly different in the two genotypic groups. In another long-term omeprazole study, we demonstrated that serum vitamin B 12 levels decreased in heterozygous extensive metabolizers, but not in extensive metabolizers with two functional CYP2C19 genes (Sagar et al. 1999). These results further strengthen the utility of determination of the CYP2C19 genotype before treatment (especially long-term) with proton pump inhibitors to adjust the dose for the individual patient. This will aid to maintain a sufficient acid inhibition with a good response and to minimize the risk to develop enterochromaffin-like cell hyperplasia and atrophic gastritis.

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Omeprazole and CYP2C19 polymorphism: effects of long‐term treatment on gastrin, pepsinogen I, and chromogranin A in patients with acid related disorders

Cited by 32 publications

References 43 publications

Effect of short-term treatment with low dosages of the proton-pump inhibitor omeprazole on serum chromogranin A levels in man

Effect of short-term treatment with low dosages of the proton-pump inhibitor omeprazole on serum chromogranin A levels in man

Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy

Dose of Proton Pump Inhibitors and the CYP2C19 Genotype

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