CYP2C19 Phenoconversion by Routinely Prescribed Proton Pump Inhibitors Omeprazole and Esomeprazole: Clinical Implications for Personalized Medicine

Abstract

The phenotype pantoprazole-13 C breath test (Ptz-BT) was used to evaluate the extent of phenoconversion of CYP2C19 enzyme activity caused by commonly prescribed proton pump inhibitors (PPI) omeprazole and esomprazole. The Ptz-BT was administered to 26 healthy volunteers and 8 stable cardiovascular patients twice at baseline and after 28 days of PPI therapy to evaluate reproducibility of the Ptz-BT and changes in CYP2C19 enzyme activity (phenoconversion) after PPI therapy. The average intrapatient interday variability in CYP2C19 phenotype (n 5 31) determined by Ptz-BT was considerably low (coefficient of variation, 17%). Phenotype conversion resulted in 25 of 26 (96%) nonpoor metabolizer (non-PM) volunteers/ patients as measured by the Ptz-BT at baseline and after PPI therapy. The incidence of PM status by phenotype following administration of omeprazole/esomeprazole (known inhibitors of CYP2C19) was 10-fold higher than those who are genetically PMs in the general population, which could have critical clinical implications for personalizing medications primarily metabolized by CYP2C19, such as clopidogrel, PPI, cyclophosphamide, thalidomide, citalopram, clonazepam, diazepam, phenytoin, etc. The Ptz-BT can rapidly (30 minutes) evaluate CYP2C19 phenotype and, more importantly, can identify patients with phenoconversion in CYP2C19 enzyme activity caused by nongenetic factors such as concomitant drugs.

Model Informed Dose Optimization of Dichloroacetate for the Treatment of Congenital Lactic Acidosis in Children

“…This postulate is consistent with an in vitro study 27 that demonstrated that the magnitude of DCAinduced inactivation effect of GSTZ1 is system specific and differs between different GSTZ1 haplotypes. Based on these findings, we hypothesize that autoinhibition phenoconverts both EGT carriers and noncarriers into slow metabolizers after repeated DCA administration, a phenomenon known as "phenoconversion," reported for many drugs [28][29][30][31] that are predominantly metabolized by phase I enzymes. However, the magnitude of phenoconversion is higher for EGT noncarriers, which converts them into ultraslow metabolizers compared with EGT carriers.…”

CYP2C19 polymorphism has no correlation with the efficacy and safety of thalidomide in the treatment of immune‐related bowel disease

“…Although mesalamine, AZA, 6‐MP or MTX are not metabolized by CYP2C19, there may be a potential interaction among the drugs. Previous studies have raised concern that proton pump inhibitors (PPIs) may diminish the clinical effectiveness of some medications, possibly by inhibiting the hepatic CYP isoenzymes . In our study, only 5 out of the 79 patients were given concomitant PPIs.…”

Absorption Differences between Immediate-Release Dexmethylphenidate and dl-Methylphenidate

“…Pharmacological benefits resulting from the chiral (or racemic) switch approach to drug discovery have many precedents, such as esomeprazole overcoming CYP2C19 polymorphism-based differences in peptic ulcer cure rates compared with omeprazole (Klieber et al, 2015) and the antidepressant escitalopram appearing to be more selective in targeting the serotonin reuptake transporter in the absence of the R-enantiomer of citalopram (Sánchez, 2006). Any potential therapeutic benefit of d-MPH over dl-MPH has been largely unknown in the literature, with the exception of overcoming absorption-phase drug interactions with ethanol (Patrick et al, 2013(Patrick et al, , 2015.…”