Effect of clopidogrel on the hydroxylation and sulfoxidation of omeprazole: A single dose study in healthy human volunteers (original) (raw)
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Effects of Omeprazole and Genetic Polymorphism of CYP2C19 on the Clopidogrel Active Metabolite
Drug Metabolism and Disposition, 2012
Clopidogrel is an antiplatelet agent widely used in cardiovascular diseases and an inactive prodrug that needs to be converted to an active metabolite in two sequential metabolic steps. Several CYP450 isoforms involved in these two steps have been described, although the relative contribution in vivo of each enzyme is still under debate. CYP2C19 is considered to be the major contributor to active metabolite formation. In the current study, net CYP2C19 contribution to the active metabolite formation was determined from exposure of the active metabolite in two clinical studies (one phase I study with well balanced genetic polymorphic populations and a meta-analysis with a total of 396 healthy volunteers) at different clopidogrel doses. CYP2C19 involvements were estimated to be from 58 to 67% in intermediate metabolizers (IMs), from 58 to 72% in extensive metabolizers (EMs), and from 56 to 74% in ultrarapid metabolizers (UMs), depending on the study and the dose. For this purpose, a static model was proposed to estimate the net contribution of a given enzyme to the secondary metabolite formation. This static model was compared with a dynamic approach (Simcyp model) and showed good consistency. In parallel, in vitro investigations showed that omeprazole is a mechanism-based inhibitor of CYP2C19 with K I of 8.56 M and K inact of 0.156 min ؊1 . These values were combined with the net CYP2C19 contribution to the active metabolite formation, through a static approach, to predict the inhibitory effect at 80-mg omeprazole doses in EM, IM, and UM CYP2C19 populations, with good consistency, compared with observed clinical values. This work was supported by sanofi-aventis and Bristol-Myers Squibb. The authors are all employees of sanofi-aventis. Editorial support was funded by sanofi-aventis and provided by Alpha-Plus Medical Communications Ltd. Article, publication date, and citation information can be found at contains supplemental material. ABBREVIATIONS: P450, cytochrome P450; clopi-H4 metabolite, active metabolite of clopidogrel (H4); PPI, proton pump inhibitor; DDI, drug-drug interaction; MBI, mechanism-based inhibition; IM, intermediate metabolizer; EM, extensive metabolizer; UM, ultrarapid metabolizer; PBPK, physiologically based pharmacokinetic; HLM, human liver microsomes; LC, liquid chromatography; MS/MS, tandem mass spectrometry; AUC, area under the plasma concentration versus time curve; PM, poor metabolizer; LLOQ, lower limits of quantification; CI, confidence interval.
British Journal of Clinical Pharmacology, 2008
The mean omeprazole AUC• of 1973 h nmol l -1 in CYP2C19*17/*17 subjects was 2.1-fold lower [95% confidence interval (CI) 1.1, 3.3] than in CYP2C19*1/*1 subjects (4151 h nmol l -1 , P = 0.04). A similar trend was observed for the sulphone metabolite with the CYP2C19*17/*17 group having a mean AUC• of 1083 h nmol l -1 , 3.1-fold lower (95% CI 1.2, 5.5) than the CYP2C19*1/*1 group (3343 h nmol l -1 , P = 0.03). A pronounced correlation (r 2 = 0.95, P < 0.0001) was seen in the intraindividual omeprazole AUC• and omeprazole sulphone AUC• values.
Pakistan journal of pharmaceutical sciences, 2018
This study was designed to evaluate a comparative single dose (40mg) pharmacokinetics (PK) of Omeprazole (OMP) and its two metabolites, 5-hydroxy Omeprazole (5-OH-OMP) and Omeprazole sulphone (OMP-S) in poor (PM) and extensive (EM) metabolizer Pakistani healthy adult volunteers. The frequency of CYP2C19 and CYP3A4 varies widely in different populations. The present study was conducted to evaluate the PK of OMP and its two metabolites in Pakistani population and to review different studies conducted after administration of single dose of OMP. Twenty two subjects were enrolled in this study and divided into two groups. The CYP2C19 phenotyping was evaluated by the metabolic ratio of OMP to 5-OH-OMP. It was a single dose, open label study and the blood samples from subjects were collected at different time intervals until 24 hours. The PK parameters were calculated using the PK-summit software. The metabolic ratio of area under the plasma concentration-time curve AUCOMP/5-OH-OMP was 1.8...
Drug Metabolism and Disposition, 2011
As a direct-acting inhibitor of CYP2C19 in vitro, lansoprazole is more potent than omeprazole and other proton pump inhibitors (PPIs), and yet lansoprazole does not cause clinically significant inhibition of CYP2C19 whereas omeprazole does. To investigate this apparent paradox, we evaluated omeprazole, esomeprazole, R-omeprazole, lansoprazole and pantoprazole for their ability to function as direct-acting and metabolism-dependent inhibitors (MDIs) of CYP2C19 in pooled human liver microsomes (HLM), as well as in cryopreserved hepatocytes and recombinant CYP2C19. In HLM, all PPIs were found to be direct-acting inhibitors of CYP2C19 with IC 50 values varying from 1.2 µM (lansoprazole; C max = 2.2 µM) to 93 µM (pantoprazole; C max = 6.5 µM). In addition, we identified omeprazole, esomeprazole, R-omeprazole, and omeprazole sulfone as MDIs of CYP2C19 (they caused IC 50 shifts after a 30-min preincubation with NADPH-fortified HLM of 4.2-, 10-, 2.5-, and 3.2-fold, respectively), whereas lansoprazole and pantoprazole were not MDIs (IC 50 shifts <1.5-fold). The MDI of CYP2C19 by omeprazole and esomeprazole was not reversed by ultracentrifugation, suggesting the inhibition was irreversible (or quasi-irreversible), whereas ultracentrifugation largely reversed such effects of R-omeprazole. Under various conditions, omeprazole inactivated CYP2C19 with K I values of 1.7-9.1 μ M and k inact values (maximal rate of inactivation) of 0.041-0.046 min-1. This study identified omeprazole, and esomeprazole, but not R-omeprazole, lansoprazole or pantoprazole, as irreversible (or quasi-irreversible) MDIs of CYP2C19. These results have important implications for the mechanism of the clinical interaction reported between omeprazole and clopidogrel, as well as other CYP2C19 substrates.
Therapeutic advances in drug safety, 2011
The recent report that clopidogrel efficacy may be more dependent on paraoxonase-1 (PON1) than on cytochrome P450 2C19 (CYP2C19) activity raises questions about the roles of these and other enzymes in clopidogrel activation. To provide insight into the emerging PON1 versus CYP2C19 debate, this commentary summarizes the clinical evidence on the pharmacokinetic determinants of clopidogrel efficacy. We then review the in vitro studies investigating the enzymes involved in clopidogrel activation, and comment on their strengths and limitations. There is agreement amongst in vitro studies regarding the involvement of CYP1A2 and CYP2B6 in the metabolism of clopidogrel to 2-oxo-clopidogrel. However, the evidence for other CYP enzymes in the first activation step (e.g. CYP2C19 and CYP3A4) is inconsistent and dependent on the in vitro test system and laboratory. All major drug metabolizing CYP enzymes are capable of converting 2-oxo-clopidogrel to sulfenic acid intermediates that subsequently...
Journal of the Brazilian Chemical Society, 2007
A simple HPLC-DAD method using a reverse phase column and isocratic elution for the simultaneous determination of omeprazole (OME), 5-hydroxyomeprazole (HOME) and omeprazole sulphone (OMES) was developed. The proposed method was used to study CYP2C19 and CYP3A4 genetic polymorphisms using OME as the probe drug in a group of Brazilian volunteers. OME, HOME and OMES were extracted from plasma samples with Tris buffer pH 9.5 (0.2 mol L -1 ) and ethyl acetate. HPLC separation was achieved using a Shim-Pack RP-18e (150 × 4.6 mm i.d., 5 μm) column, with acetonitrile phosphate buffer pH 7.6 (24:76) as mobile phase and total run time of 15 min. Retention times were 2.7 min for internal standard (sulpiride), 4.1 min for HOME, 11.6 min for OME and 12.6 min for OMES. Detection (UV at 302 nm) of analytes was linear in the range from 25 to 1000 ng mL -1 . Extraction recoveries were in the range of 64.3 to 73.2% for all analytes. A group of 38 Brazilian healthy volunteers was phenotyped with this method, after a single oral dose of 20 mg omeprazole. The method presented adequate accuracy and precision, with limit of quantification of 25 ng mL -1 for omeprazole and metabolites, which allowed the identification of ultra-rapid metabolizers for both CYP2C19 and CYP3A4 and took advantage of the selective identification offered by diode-array detectors.
Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism
British Journal of Clinical Pharmacology, 1993
1. The in vitro metabolism of omeprazole was studied in human liver microsomes in order to define the secondary metabolic pathways and identify the cytochrome P450 (CYP) isoforms responsible for the formation of the secondary metabolites of omeprazole. 2. The major secondary omeprazole metabolite was the hydroxysulphone, which was formed during incubation with both hydroxyomeprazole and omeprazole sulphone. A second metabolite, tentatively identified as pyridine-N-oxide omeprazole sulphone, was also formed during incubation with omeprazole sulphone. The formation kinetics of these two metabolites from omeprazole sulphone were biphasic suggesting the involvement of multiple CYP isoforms in each case. In contrast, the formation kinetics of hydroxysulphone from hydroxyomeprazole were linear. 3. Inhibition studies, performed with omeprazole sulphone as substrate at concentrations at which the high affinity activities predominated, with a series of isoform selective inhibitors as well as with an anti-CYP2C3 antibody suggested a dominant role of S-mephenytoin hydroxylase in the formation of hydroxysulphone from omeprazole sulphone. By contrast, CYP3A activities were predominant in the formation of hydroxysulphone from hydroxyomeprazole as well as in the formation of pyridine-N-oxide omeprazole sulphone from omeprazole sulphone.
The hydroxylation of omeprazole correlates with S -mephenytoin and proguanil metabolism
European Journal of Clinical Pharmacology, 1997
Objectives: This pharmacogenetic study was aimed at studying the pattern of oxidation of omeprazole in a Turkish population and testing whether omeprazole metabolism cosegregates with the genetically determined metabolism of mephenytoin and proguanil in Turkish subjects. Methods: The hydroxylation of omeprazole was measured in 116 unrelated healthy Turkish subjects after administration of a single oral dose of omeprazole (20 mg), using the ratio of omeprazole to 5-hydroxyomeprazole in plasma 3 h after dosing. To 31 subjects, who were phenotyped with omeprazole, mephenytoin (100 mg, p.o.) or proguanil (200 mg, p.o.) were administered at least 1 week apart. The S/R ratio of mephenytoin and the ratio of proguanil to cycloguanil were determined from an 8-h urine collection. Results: Based on the distribution of the log (omeprazole/hydroxyomeprazole) values and using the antimode value of 0.8, the frequency of poor metabolizers of omeprazole was estimated to be 7.7% (95% con®dence interval 3±18%) which was similar to that in the other Caucasian populations (P = 0.54, Fisher's exact test). Three poor metabolizers of omeprazole were also clas-si®ed as poor metabolizers of both mephenytoin and proguanil and no misclassi®cation occurred with three phenotyping methods. All three methods separated poor or extensive metabolizer phenotypes with complete concordance. The ratio of omeprazole to hydroxyomeprazole correlated with the S/R ratio of mephenytoin and the ratio of proguanil to cycloguanil.
Interaction between Omeprazole and Gliclazide in Relation to CYP2C19 Phenotype
2021
The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed PBPK models were verified using in vivo pharmacokinetic profiles obtained from a clinical trial on omeprazole-gliclazide interaction in healthy volunteers, CYP2C19 normal/rapid/ultrarapid metabolizers (NM/RM/UM). In addition, the association of omeprazole cotreatment with gliclazide-induced hypoglycemia was explored in 267 patients with type 2 diabetes (T2D) from the GoDARTS cohort, Scotland. The PBPK simulations predicted 1.4–1.6-fold higher gliclazide area under the curve (AUC) after 5-day treatment with 20 mg omeprazole in all CYP2C19 phenotype groups except in poor metabolizers. The predicted gliclazide AUC increased 2.1 and 2.5-fold in intermediate metabolizers, and ...