Effects of omeprazole and cimetidine on the urinary metabolic ratio of proguanil in healthy volunteers

1. Despite speculation that the CYP2C19 gene may contain CpG islands, there has been little direct assessment of the role for epigenetics in the regulation of this pharmacogene. The effect of 5-aza-2'-deoxycytidine (5azaDC), a DNA methyltransferase inhibitor, and trichostatin A (TSA), an inhibitor of histone deacetylases, on the expression of CYP2C19 and five of its known transcription factors (TF) has been assessed in cell lines derived from neoplastic liver and intestine. 2. CYP2C19 mRNA was substantially up-regulated (>18-fold) after treatment with 5azaDC despite the fact that the two intronic CpG islands in this gene remained substantially methylated (>50%). The TF NR1I3 was also consistently up-regulated after treatment with 5azaDC. NR1I3 lacks CpG islands in the proximal promoter region and is therefore not likely to be directly regulated by DNA methylation. Therefore, it appears that 5azaDC treatment affects an unidentified upstream regulator of both CYP2C19 and/or NR1I3. This is supported by the fact that the relationships between TF for CYP2C19 and the expression of this target gene in human liver samples only accounted for ∼70% of the variability of CYP2C19 mRNA levels. These data suggest that an yet un-identified 'master regulator' of CYP2C19 transcription could itself be a target of epigenetic control.

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Indirect regulation ofCYP2C19gene expression via DNA methylation

Burns

Shepherd

Finlay

et al. 2017

Xenobiotica

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No Dose Adjustment on Coadministration of the PDE4 Inhibitor Roflumilast With a Weak CYP3A, CYP1A2, and CYP2C19 Inhibitor: An Investigation Using Cimetidine

Böhmer

Gleiter

Mörike

et al. 2011

The Journal of Clinical Pharmacology

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This nonrandomized, fixed-sequence, 2-period crossover study investigated potential pharmacokinetic interactions between the phosphodiesterase 4 inhibitor roflumilast, currently in clinical development for the treatment of chronic obstructive pulmonary disease, and the histamine 2 agonist cimetidine. Participants received roflumilast, 500 µg once daily, on days 1 and 13. Cimetidine, 400 mg twice daily, was administered from days 6 to 16. Pharmacokinetic analysis of roflumilast and its active metabolite roflumilast N-oxide was performed, and the ratio of geometric means for roflumilast alone and concomitantly with steady-state cimetidine was calculated. The effect of cimetidine on the total PDE4 inhibitory activity (tPDE4i; total exposure to roflumilast and roflumilast N-oxide) was also calculated. Coadministration of steady-state cimetidine increased mean tPDE4i of roflumilast and roflumilast N-oxide by about 47%. The maximum plasma concentration (C(max)) of roflumilast increased by about 46%, with no effect on C(max) of roflumilast N-oxide. The increase in tPDE4i of roflumilast and roflumilast N-oxide following coadministration with cimetidine was mainly due to the inhibitory effect of cimetidine on cytochrome P450 (CYP) isoenzymes CYP1A2, CYP3A, and CYP2C19. These moderate changes indicate that dose adjustment of roflumilast is not required when coadministered with a weak inhibitor of CYP1A2, CYP3A, and CYP2C19, such as cimetidine.

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Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism

Desta

Zhao

Shin

et al. 2002

Clinical Pharmacokinetics

830

577

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Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity. In EMs, approximately 80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately 5000 US dollars for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs. Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal. Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.

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Effects of omeprazole and cimetidine on the urinary metabolic ratio of proguanil in healthy volunteers

Abstract: The concomitant administration of omeprazole or cimetidine will not result in phenocopying extensive metabolisers of proguanil, although cimetidine inhibits the formation of cycloguanil in extensive metabolisers.

Cited by 3 publications

References 13 publications

Indirect regulation ofCYP2C19gene expression via DNA methylation

Indirect regulation ofCYP2C19gene expression via DNA methylation

No Dose Adjustment on Coadministration of the PDE4 Inhibitor Roflumilast With a Weak CYP3A, CYP1A2, and CYP2C19 Inhibitor: An Investigation Using Cimetidine

Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism

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