Pharmacodynamics Of Proton Pump Inhibitors Research Articles

Effect of Food and Dosing Regimen on Safety and Efficacy of Proton Pump Inhibitors Therapy—A Literature Review

Proton pump inhibitors (PPIs) are the first-choice drugs used to prevent and treat acid-related diseases. However, a lack of satisfactory response to the standard PPI dose (“PPI failure”) is often reported, especially in patients with gastroesophageal reflux disease. Poor compliance seems to be one of the main causes of PPI failure; hence, it is crucial to gain knowledge on how to properly administer PPIs. In this review, we aimed to evaluate the effect of food, beverages, and dosing regimen on pharmacokinetics and pharmacodynamics of PPIs and to frame recommendations for healthcare professionals to improve both patient’s counseling and compliance to treatment with PPIs. A total of 201 papers were identified following a literature search. After full-text evaluation, 64 studies were included in the review. Co-administration of PPIs with a meal may affect both their bioavailability and effectiveness; however, the influence of food depends on the type of drug and its formulation. Except for pantoprazole, PPIs can be administered in the morning or evening; however, morning intake generally provides better daytime control of gastric acidity. In most cases, the choice of the proper schedule of administration should be based on the patient’s symptoms and individual dosing preferences.

Reply to: Letter to the Editor “Impact of the CYP2C19*17 Polymorphism on the Pharmacokinetics and Pharmacodynamics of Proton Pump Inhibitors”

We are pleased to read the commentary from Dr. Maryann and Dr. John on our paper,1 where they argue that: “The authors' conclusion that the pharmacokinetics and pharmacodynamics of ilaprazole are not affected by polymorphisms of the CYP2C19 is limited by the fact that they did not include the CYP2C19*17 in the investigation.” First we agree with them that CYP2C19*17 is associated with ultra-rapid metabolism (UM) of proton pump inhibitors (PPIs) and known for its great diversity among different ethnic groups. However, its clinical significance is estimated to be considerably smaller than that of CYP2C19*2 and *3.2 More importantly, our clinical trial was designed to study whether or not CYP2C19 genetic polymorphisms affect ilaprazole metabolism (so that the involvement of CYP2C19 can be indirectly tested), rather than to quantify the genetic effect of any specific polymorphism. Dividing subjects into homo EM (CYP2C19*1/*1), hetero EM (CYP2C19*1/*2 and *1/*3), and PM (CYP2C19*2/*2 and *2/*3) groups successfully created a CYP2C19 activity gradient, which would have shown differences of ilaprazole PK/PD among the three groups if CYP2C19 was significantly involved in ilaprazole metabolism. This similar study design has been widely applied in other clinical trials.3, 4 In addition, including CYP2C19 UMs into our study was unrealistic, since Koreans have much lower CYP2C19*17 frequency compared with Caucasians (∼1% vs. ∼20%)5; according to our unpublished data: the CYP2C19*17 allele frequency is 0.7% and the CYP2C19*1/*17 genotype frequency is 0.2%. On the other hand, our study focused on CYP2C19 but not other CYPs because our hypothesis was based on the fact that CYP2C19 is the major enzyme catalyzing all the other PPIs. Interestingly, our in vitro study later found that ilaprazole, unlike other PPIs, is predominantly metabolized by CYP3A4/5, with negligible involvement of other CYPs.6 This in vitro study not only supports our previous conclusion but also suggests CYP2C19*17 unlikely alter ilaprazole disposition. In summary, our clinical trial design, even without including CYP2C19*17, has sufficiently served the study purpose; moreover the minimal involvement of CYP2C19 in ilaprazole metabolism suggests our conclusion would not be discredited by the fact we didn't include CYP2C19*17. Once again we very much appreciate Dr. Maryann and Dr. John's rigorous attitude and hope our reply answers their question.

Impact of the CYP2C19*17 Polymorphism on the Pharmacokinetics and Pharmacodynamics of Proton Pump Inhibitors

Impact of the CYP2C19*17 Polymorphism on the Pharmacokinetics and Pharmacodynamics of Proton Pump Inhibitors

Effect of CYP2C19 Genetic Polymorphism on Pharmacokinetics and Pharmacodynamics and Pharmacodynamics of a New Proton Pump Inhibitor, Ilaprazole

It is well known that the CYP2C19 genetic polymorphism influences the pharmacokinetics and pharmacodynamics of proton pump inhibitors (PPIs), but no report has addressed the effects on ilaprazole, a newly developed PPI. To investigate the effects of the CYP2C19 genetic polymorphism on the disposition and pharmacodynamics of ilaprazole, multiple doses of once-daily 10 mg ilaprazole were repeatedly administered for 7 days to 27 healthy Korean participants, comprising 9 homozygous CYP2C19 extensive metabolizers (homo EMs), 10 heterozygous EMs (hetero EMs), and 8 homozygous poor metabolizers (PMs). The plasma concentration and pharmacodynamic response were measured in the last dose interval. Each genotype group was matched for gender and thus was composed of 4 male and 4 female participants when the analysis was conducted. The pharmacokinetic parameters estimated from the plasma concentrations of ilaprazole and its metabolite ilaprazole sulfone, the serum gastrin level, and the 24-hour intragastric pH were compared among the CYP2C19 genotype groups. No statistically significant differences in the maximum plasma concentration at steady state(C(ss,max)) and the area under the concentration-time curve from zero to 24 hours (AUC(τ)) of ilaprazole and ilaprazole sulfone were observed among the homo EM, hetero EM, and PM CYP2C19 genotypes. In addition, the mean 24-hour intragastric pH, the percentage of time at pH >4, and the AUC(τ) of serum gastrin showed no significant differences among the CYP2C19 genotype groups. The data suggests that the pharmacokinetics and pharmacodynamics of ilaprazole are not significantly influenced by the CYP2C19 genetic polymorphism in healthy participants.

CYP2C19 genotypes in the pharmacokinetics/pharmacodynamics of proton pump inhibitor-based therapy of Helicobacter pylori infection

Importance of the field: Proton pump inhibitors (PPIs) are potent gastric acid inhibitors. Therapies with a PPI and antibiotics are used to cure Helicobacter pylori (H. pylori) infection, which is closely related to many gastrointestinal diseases. Most PPIs are mainly metabolized by cytochrome 2C19 (CYP2C19). The genetic polymorphisms of CYP2C19 may lead to the differences in pharmacokinetics (PK), pharmacodynamics (PD) and clinical efficacy of PPIs.Areas covered in this review: The roles of PPIs on the eradication of H. pylori are summarized. The impact f CYP2C19 polymorphism on the PK and PD of PPIs is addressed and related to the present status of therapy for H. pylori infection. The opinions on the strategy of PPIs-based therapies of H. pylori infection are provided.What the reader will gain: Update the factors that may influence the PPIs-based therapies of H. pylori infection.Take home message: The eradication rates of H. pylori infection are significantly different between patients who are CYP2C19 extensive metabolizers and poor metabolizers, partly because of the differences in the PK and PD of PPIs. Nonetheless, the differences can be improved by adjusting the regimens of PPIs and using antibiotics that have less H. pylori-resistance.

Review article: relationship between the metabolism and efficacy of proton pump inhibitors – focus on rabeprazole

Proton pump inhibitors are now considered the mainstay of treatment for acid-related disease. Although all proton pump inhibitors are highly effective, the antisecretory effects of different drugs in this class are not completely consistent across patients. One reason for this is the acid-suppressing effect of Helicobacter pylori infection, which may augment the actions of proton pump inhibitors. A second important reason for interpatient variability of the effects of proton pump inhibitors on acid secretion involves genetically determined differences in the metabolism of these drugs. This article focuses on the impact of genetic polymorphism of cytochrome P450 (CYP)2C19 on the pharmacokinetics and pharmacodynamics of proton pump inhibitors, particularly rabeprazole. Results reviewed indicate that the metabolism and pharmacokinetics of rabeprazole differ significantly from those of other proton pump inhibitors. Most importantly, the clearance of rabeprazole is largely nonenzymatic and less dependent on CYP2C19 than other drugs in its class. This results in greater consistency of pharmacokinetics for rabeprazole across a wide range of patients with acid-related disease, particularly those with different CYP2C19 genotypes. The pharmacodynamic profile for rabeprazole is also characterized by more rapid suppression of gastric acid secretion than with other proton pump inhibitors, which is also independent of CYP2C19 genotype. The favourable pharmacokinetic/pharmacodynamic profile for rabeprazole has been shown to result in high eradication rates for H. pylori in both normal and poor metabolizers. Pharmacodynamic results have also suggested that rabeprazole may be better suited than omeprazole as on-demand therapy for symptomatic gastro-oesophageal reflux disease. Finally, the use of rabeprazole is not complicated by clinically significant drug-drug interactions of the type that have been reported for omeprazole.