Effects of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of proton pump inhibitors

Journal Pre-proof Effects of Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Proton Pump Inhibitors He-Jian Zhang, Xue-Hui Zhang, Jie Liu, Lu-Ning Sun, Yi-Wen Shen, Chen Zhou, Hong-Wen Zhang, Li-Jun Xie, Juan Chen, Yun Liu, Yong-Qing Wang

PII:

S1043-6618(19)31318-0

DOI:

https://doi.org/10.1016/j.phrs.2019.104606

Reference:

YPHRS 104606

To appear in:

Pharmacological Research

Received Date:

11 July 2019

Revised Date:

13 December 2019

Accepted Date:

13 December 2019

Please cite this article as: Zhang H-Jian, Zhang X-Hui, Liu J, Sun L-Ning, Shen Y-Wen, Zhou C, Zhang H-Wen, Xie L-Jun, Chen J, Liu Y, Wang Y-Qing, Effects of Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Proton Pump Inhibitors, Pharmacological Research (2019), doi: https://doi.org/10.1016/j.phrs.2019.104606

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Effects of Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Proton Pump Inhibitors He-Jian Zhang1,2, Xue-Hui Zhang3*, Jie Liu4, Lu-Ning Sun1, Yi-Wen Shen1, Chen Zhou1, Hong-Wen Zhang1, Li-Jun Xie1, Juan Chen1, Yun Liu5#, Yong-Qing Wang1,3# 1

Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing

Medical University & Jiangsu Province Hospital, Nanjing, China Xuzhou Medical University, Xuzhou, China

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Department of Pharmacy, Jiangsu Shengze Hospital, Nanjing Medical University,

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2

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Suzhou, China

Pukou Branch, the First Affiliated Hospital of Nanjing Medical University, Nanjing,

Department of Geriatrics endocrinology, the First Affiliated Hospital of Nanjing

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5

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China

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Medical University & Jiangsu Province Hospital, Nanjing, China

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Co-first author: Xue-Hui Zhang and He-Jian Zhang contributed equally to this work

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as co-first authors.

Co-correspondence authors.

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Corresponding author:

Yong-Qing Wang, PhD, Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing 210029, China. E-mail address: [email protected]. Yun Liu, PhD, Department of Geriatrics endocrinology, the First Affiliated Hospital of 1

Nanjing Medical University & Jiangsu Province Hospital, E-mail address: [email protected].

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Graphical abstract

Abstract

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Proton pump inhibitors (PPIs) are used widely for the treatment of acid-related

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disorders. Despite their excellent efficacy and tolerance, the pharmacodynamics and pharmacokinetics of PPIs are affected by each patient’s CYP2C19 and gastric

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H+,K+-ATPase genotype. The aim of this review was to analyze the effect of genetic polymorphisms on the pharmacodynamic and pharmacokinetic properties of PPIs.

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The gastric acid-suppressive effect of PPIs is affected by both gastric H+,K+-ATPase and CYP2C19 polymorphisms, although gastric H+,K+-ATPase polymorphisms may have larger effects. Ilaprazole and rabeprazole show relatively small differences in the pharmacokinetic and pharmacodynamic properties and clinical efficacy among the different CYP2C19 genotypes. Compared with oral administration, the intravenous 2

infusion of PPIs is less affected by CYP2C19 polymorphism. At the same dose, each enantiomer has less variation among different CYP2C19 genotypes than a racemate mixture. Keywords: Proton pump inhibitors (PPIs), CYP2C19, gastric H+,K+-ATPase, Polymorphism, Pharmacokinetics, Pharmacodynamics

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Chemical compounds

Omeprazole (PubChem CID: 4594); Esomeprazole (PubChem CID: 9568614);

Lansoprazole (PubChem CID: 3883); Dexlansoprazole (PubChem CID: 9578005);

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Pantoprazole (PubChem CID: 4679); Rabeprazole (PubChem CID: 5029); Ilaprazole

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(PubChem CID: 214351).

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Abbreviations

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PPIs: proton pump inhibitors; H. pylori: Helicobacter pylori; H+,K+-ATPase: hydrogen-potassium adenosine triphosphatase; CYP450: cytochrome P450; PK:

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pharmacokinetic; PD: pharmacodynamic; UMs: ultra-rapid metabolizers; homEMs: homozygous extensive metabolizers; hetEMs: heterozygous extensive metabolizers;

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PMs: poor metabolizers; AUC: area under the concentration versus time curve; Cmax: maximum plasma concentration; t1/2: elimination half-life; TpH>4 (%): percentage time of intragastric pH>4.0; MR: metabolic rate; H2RAs: histamine 2 receptor antagonists; SNPs: single nucleotide polymorphisms.

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Introduction Proton pump inhibitors (PPIs) are a class of acid-suppressing drugs that is used widely for the treatment of acid-related disorders, such as peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome[1-3]. In addition to the general therapy for acid-related diseases, PPIs can also be used to treat other diseases, such as Helicobacter pylori (H. pylori) infection, cancer, and viral

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infections[4].

Gastric hydrogen-potassium adenosine triphosphatase (H+,K+-ATPase, proton

pump), an α, β-heterodimeric enzyme, has a key role in the secretion of gastric acid.

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PPIs are benzimidazole-based compounds that suppress gastric acid secretion by

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irreversibly blocking the gastric H+,K+-ATPase after the drug is converted into its active form in gastric parietal cells[5], as the active sulfonamide formulation can

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covalently bind to H+,K+-ATPase. Not all PPIs bind to the same cysteines: rabeprazole

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binds to cysteines 813, 892, 822, and 321; lansoprazole binds to cysteines 813, 892, and 321; omeprazole binds to cysteines 813 and 892; and pantoprazole binds to

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cysteines 813 and 822. In some cases, the affinity of PPIs decreases, which may lead to a reduction in acid inhibition efficacy[6, 7].

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Cytochrome P450 (CYP450) enzymes are responsible for the metabolism of a

majority of therapeutic drugs and have important roles in bioavailability, elimination, and drug-drug interactions. PPIs are mainly metabolized by CYP450 enzymes; CYP2C19 and CYP3A4/5 are the two main isoenzymes of the CYP superfamily that mediate the hydroxylation and sulfoxidation of PPIs[8]. These enzymes are expressed 4

in humans and may influence both the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of PPIs[9]. Most clinical research has reported CYP2C19 genotypes by using star (*) allele nomenclature; the main alleles and their respective influences on the activity of CYP2C19 enzymes are shown in Figure 1. The genotypes of CYP2C19 are classified as ultra-rapid, homozygous extensive, heterozygous extensive or poor metabolizers, depending on the genotypic combination of an individual. Individuals

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with the higher activity allele (*17) are classified as ultra-rapid metabolizers (UMs). CYP2C19*17 is a gain-of-function allele, which is thought to increase the clearance and reduce plasma concentrations of PPIs compared with the normal allele.

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Individuals with two normal (non-mutant, *1/*1) alleles are classified as homozygous

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extensive metabolizers (homEMs), and are able to produce an abundance of enzymes and to metabolize PPIs at a faster rate, which may lower the anti-secretory efficacy of

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PPIs. Individuals with one normal function allele and one no-function allele (taure 1)

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are classified as heterozygous extensive metabolizers (hetEMs), whereas individuals with two copies of the CYP2C19 no-function allele are classified as poor metabolizers

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(PMs). CYP2C19 PMs have a much slower rate of metabolism, conferring greater bioavailability and subsequently increasing the anti-secretory efficacy of PPIs[10-12].

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There are marked geographic differences in the frequency distribution of these genotypes[11-15]. The frequency of PMs is much higher in Asian populations, such as Japanese and Chinese populations, than in American, white European, or African populations (Table 1)[12]. Previous studies have reported significant relationships between CYP2C19 polymorphisms and PK/PD parameters after the administration of 5

omeprazole[16], rabeprazole[17, 18], lansoprazole[19, 20], and pantoprazole[21]. This review has focused on the differences in PK/PD parameters and clinical efficacy of different PPIs among the different genotypes of CYP2C19 and gastric H+,K+-ATPase. In addition, we evaluated the literature related to administration methods to determine the underlying patterns of how genetic polymorphisms affect

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the PK/PD of PPIs.

Figure 1. Allelic variants and genotypes of CYP2C19. UMs: Ultra-metabolisers; HomEMs:

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homozygous extensive metabolizers; HetEMs: heterozygous extensive metabolizers; PMs: poor metabolizers. See http://www.cypalleles.ki.se/cyp2c19.htm for updates on CYP2C19 allelic variants and nomenclature.

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Table 1. Frequencies of CYP2C19 genotypes among different races[11-15]. Phenotype

Ratio

Metabolism of PPIs

Asian

Caucasian

African

UMs

2%-17%

26%-34%

9%-28%

At highest rates

HomEMs

23%-53%

41%-70%

29%-42%

At higher rates

HetEMs

35%-55%

22%-30%

32%-49%

At moderate rates

PMs

10%-23%

1%-5%

3%-4%

At lowest rates

UMs: Ultra-metabolisers; HomEMs: homozygous extensive metabolizers; HetEMs: heterozygous

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extensive metabolizers; PMs: poor metabolizers.

Omeprazole

Omeprazole, a first-generation PPI, is the most extensively studied PPI for the

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treatment of acid-related diseases[22]. Omeprazole is mainly metabolized by CYP2C19 to hydroxyomeprazole, and partially metabolized by CYP3A4 to

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omeprazole sulfone, which is subsequently metabolized by CYP2C19 to

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hydroxyomeprazole sulfone[23] (Figure 2). The success rate of H. pylori eradication may be impacted by the CYP2C19 genotype; the eradication rates of the five main

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PPIs are summarized in Table 2. In addition, the PK/PD parameters and clinical efficacy of omeprazole are significantly impacted by the genetic polymorphism of

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CYP2C19. The PK parameters (AUC, Cmax, t1/2, and clearance) and PD properties

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(TpH>4 (%) and 24-h median intragastric pH) were significantly different between CYP2C19 PMs and homEMs after a single dose of oral omeprazole (Table 3)[24, 25]. The mean area under the concentration versus time curve (AUC) of omeprazole after a single oral dose in homEMs was much lower than that in PMs; the ratios of maximum plasma concentration (Cmax) and elimination half-life (t1/2) value in PMs vs. homEMs for omeprazole were consistent with the observations in AUC; in addition, 7

homEMs exhibited significantly higher clearance than PMs (Table 3). The difference in mean AUC after a single intravenous dose was relatively small among CYP2C19 genotypes, although the mean AUC in PMs was still higher than that in EMs[16, 26]. The difference in relative AUC ratios after oral dosing among different CYP2C19 genotypes is greater than that after intravenous dosing. One possible explanation may be the absence of inter-formulation and inter-individual differences in the absorption

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of omeprazole when using an intravenous dosage form. PPIs (such as omeprazole)

reach maximal plasma concentrations within 2 h after oral dosing and are eliminated from systemic circulation quickly. The PK/PD parameters after single oral, single

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intravenous, repeated oral, and repeated intravenous doses of omeprazole in different

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genotypes are summarized in Table 3. After repeated doses, similar differences in 24-h median pH and the percentage time of intragastric pH>4.0 (TpH>4 (%)) were observed

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among different CYP2C19 genotypes[15, 16, 24, 27-32]. There is a greater gastric

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acid-suppression effect in PMs than in EMs, which is in accordance with the rate of H. pylori eradication shown in Table 2. A significant increase in 24-h median pH in EMs

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was observed during the progression from single dose to repeated doses, and the PK parameters of omeprazole were also different between single dose and repeated doses,

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with a significantly higher Cmax and AUC after repeated omeprazole dosing in EMs, but not in PMs[16]. The current PPIs on the market have a relatively short t1/2 of 1–2 h, which means they are cleared quickly from the blood. However, PK parameters (AUC, Cmax, t1/2, and clearance) reveal a significant accumulation in EMs after repeated doses of PPIs. 8

This may be because PPIs are inhibitors of hepatic microsomal enzymes, which leads to the inhibition of CYP2C19 enzymes after repeated doses. In addition, only the pumps that are active can be inhibited on the first day of once-a-day dosing, and not all pumps are active. On the second day, more newly activated pumps may be inhibited by PPIs. Generally, at steady-state, 70% of the pump population is inhibited by the third day[16, 33].

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Owing to the specific binding between drugs and molecules (e.g., transporters, receptors, enzymes, and DNA), the metabolic process and clinical efficacy of PPIs may differ between individual stereoisomers and racemic mixtures, even if the

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different stereoisomers have equal pharmacological activity[22, 34-36]. Esomeprazole,

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the S-isomer of omeprazole, is a more potent acid inhibitor than omeprazole and was first marketed in America in 2001[22, 37]. It is also metabolized by CYP2C19, but the

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clearance is lower than that of omeprazole. In a comparison of the acid-inhibitory

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effect between esomeprazole and omeprazole, CYP2C19 genotype-dependent differences were found to be smaller after the oral administration of esomeprazole (20

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mg twice daily), although there was no significant difference between esomeprazole and omeprazole in TpH>4 (%). In addition, in HomEMs, the median 24-h intragastric

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pH on Day 7 with esomeprazole was significantly higher than that with omeprazole[30]. No significant difference in the acid-suppression effect was observed between homEMs and hetEMs after either a single dose or repeated dosing (5 days) of esomeprazole. The plasma levels were higher after repeated intravenous dosing than after single dose administration as the clearance was decreased by 29%; thus, the 9

increased AUC of esomeprazole following repeated doses is probably due to a combination of a decreased systemic clearance and a decrease in first-pass

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elimination[38].

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Figure 2. Metabolic pathways of omeprazole. The thicker the arrow, the larger the contribution of

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the CYP isoforms to the metabolic pathway.

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Table 2. H. pylori eradication rates in different treatment regimens according to CYP2C19 Genetic Polymorphisms Compound

HomEMs

HetEMs

PMs

Omeprazole[39-42]

61%-85%

83%-90%

100%

Lansoprazole[43, 44]

74%-80%

81%-98%

85%-100%

Pantoprazole[45-47]

69%-87%

77%-84%

82%-100%

Rabeprazole[40, 44, 45, 48, 49]

60%-89%

62%-97%

72%-100%

Esomeprazole[49]

73%-88%

91%-95%

90%-100%

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HomEMs: homozygous extensive metabolizers; HetEMs: heterozygous extensive metabolizers;

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PMs: poor metabolizers.

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Table 3. Differences in pharmacokinetic and pharmacodynamic parameters for PPIs according to CYP2C19 polymorphisms.

Pantoprazole[65-68]

24-h Median pH

TpH> 4(%)

HomEMs:HetEMs:PMs

HomEMs:HetEMs:PMs

HomEMs:HetEMs:PMs

HomEMs:HetEMs:PMs

HomEMs:HetEMs:PMs

HomEMs:HetEMs:PMs

1.0:(1.1-3.7):(1.4-20.0) 1.0:(1.5-1.7):(1.5-4.3)) 1.0:(1.3-5.3):(2.0-13.1) 1.0:(1.0-1.3):(1.4-4.8) 1.0:(1.4-2.1):(3.7-8.5) 1.0:(1.4-1.8):(2.8-4.0) 1.0:1.7:3.9 1.0:(4.2-7.4)* 1.0:(1.2-2.9):(1.4-5.1) 1.0:(2.3-3.2):(4.1-4.9) 1.0:(1.0-2.3):(1.2-4.3) 1.0:(1.1-3.0):(1.7-5.3) -

1.0:(1.1-2.6):(1.8-7.6) 1.0:1.1:1.2 1.0:(1.3-2.5):(1.5-4.3) 1.0:1.2:1.4 1.0:(1.1-1.7):(1.6-2.8) 1.0:(1.2-1.5):(1.1-1.4) 1.0:1.3:2.0 1.0:(1.4-1.8) * 1.0:1.2:1.2 1.0:3.0:3.8 1.0:(1.1-1.7):(1.8-3.6) 1.0:(1.5-2.3):(2.2-4.1) -

1.0:(0.7-2.7):(1.2-3.8) 1.0:(1.0-1.3):(1.3-2.7) 1.0:(1.0-1.9):(1.0-3.5) 1.0:1.2:1.2 1.0:(1.0-2.1):(1.9-5.6) 1.0:(1.2-1.4):(3.1-3.5) 1.0:1.3:3.3 1.0:(2.2-3.5) * 1.0:1.3:5.7 1.0:(1.3-3.4) * 1.0:(1.1-2.3):(1.3-3.8) 1.0:(1.0-1.9):(1.2-3.2) -

(3.6-20.7):(3.2-5.9):1.0 (1.4-6.4):(1.4-4.0):1.0 (4.2-13.5):(2.5-2.7):1.0 1.1:1.1:1.0 (3.4-8.5):(2.4-4.3):1.0 (2.9-3.2):(1.5-2.2):1.0 3.2:2.0:1.0 4.7:2.9:1.0 5.8:4.0:1.0 (1.6-4.2):1.0* (1.6-5.2):(1.3-2.8):1.0 3.8:3.2:1.0 -

(0.9-4.4):(1.1-6.8):(1.3-6.7) (2.6-4.7):(4.3-6.3):(5.3-7.4) (1.5-5.9):(1.6-6.6):(4.0-7.6) (2.6-6.1):(4.3-6.8):(5.3-7.5) (3.6–4.8):(4.4–5.8):(5.0–6.4) (4.2-7.6):(6.2-7.8):(5.5-7.9) (3.5-5.5):(3.4-6.9):(4.7-7.3) (3.8–4.1):(3.4–5.0):(5.0–6.1) (2.7-6.9):(2.9-6.7):(6.6-7.2) 4.1:(6.1-6.2):(4.9-5.6) (4.2-8.0):(5.6-7.4):(6.0-6.6) (2.1-5.2):(2.0-6.0):(3.1-6.8) (2.1-6.4):(2.9-6.5):(4.1-7.4) -

(14-32):(27-53):(19-78) 59:66:79 (23-62):(24-75):(48-95) (58-78):(80-86):(93-94) 20:16# 73:86:85 (26-61):(37-69):(72-93) 49:75:90 32:48:44 64:66:100 44:54:60 84:93:99 (45-53):(51-68):(68-89) (36-75):(53-78):(53-91) -

pr

clearance

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Rabeprazole[18, 69-79]

t1/2

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Lansoprazole[7, 19, 20, 57-64]

Single oral dose Single intravenous dose Repeated oral dose Repeated intravenous dose Single oral dose Single intravenous dose Repeated oral dose Repeated intravenous dose Single oral dose Single intravenous dose Repeated oral dose Repeated intravenous dose Single oral dose Single intravenous dose Repeated oral dose Repeated intravenous dose

Cmax

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Omeprazole[10, 14-17, 20, 24-32, 50-56]

AUC

Pr

compound

AUC: Area under the concentration versus time curve; Cmax: Maximum plasma concentration; t1/2: elimination half-life; Median pH: median pH value; TpH> 4(%): percent of time that intragastric pH is above 4.0. HomEMs: homozygous extensive metabolizers; HetEMs: heterozygous extensive metabolizers; PMs, poor metabolizers. Pharmacokinetic data is standardized with homEM (Cmax, AUC, t1/2) or PM (Clearance) in each study to visualize the effects of polymorphisms on pharmacokinetic parameters of PPIs. * Relative ratios between EMs and PMs. # Relative ratios between HomEMs and HetEMs.

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Lansoprazole Lansoprazole, another first-generation PPI, is also a benzimidazole derivative. It has been used widely for the treatment of H. pylori infection (in combination with amoxicillin and clarithromycin), gastroesophageal reflux, and other acid-related disorders[80]. There are significant inter-individual differences in the PK of lansoprazole and its metabolites, which are related to genetic polymorphisms of

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CYP450; a summary of PK/PD parameters of lansoprazole is shown in Table 3.

Lansoprazole is predominantly metabolized to 5'-hydroxy lansoprazole by CYP2C19

through hydroxylation, lansoprazole sulfone by CYP3A4/5 through sulfoxidation, and

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then further hydroxylated to its 5'-hydroxy metabolite by CYP2C19 (Figure 3). When

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administered orally, the hydroxylation of lansoprazole was significantly influenced by CYP2C19 polymorphisms, and PMs exhibited a greater AUC and longer t1/2 than

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homEMs and hetEMs[19, 54, 61]. In terms of the main metabolites (5'-hydroxy

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lansoprazole and lansoprazole sulfone), the metabolic rate (MR) of the conversion of lansoprazole to 5'-hydroxy lansoprazole is lower in PMs, whereas the MR of

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lansoprazole to lansoprazole sulfone is markedly higher. The metabolic ratio of lansoprazole to lansoprazole sulfone of PMs was approximately 12.6-fold higher than

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that of EMs[19, 57, 62]. The Tmax of lansoprazole sulfone in CYP2C19 PMs was approximately 4 h, but approximately 0.76 h in EMs. In particular, the AUC and Cmax of lansoprazole sulfone in CYP2C19 PMs were approximately 75.1- and 8.7-fold higher than those in EMs, which means that CYP2C19 polymorphisms have a significant effect on the metabolic process of lansoprazole in vivo[81]. Compared 13

with homEMs, the PK parameters (AUC, Cmax, and t1/2) of lansoprazole are markedly higher in PMs after single oral administration; these results are summarized in Table 3. There was no significant difference between homEMs and hetEMs, whereas the clearance of lansoprazole was significantly lower in PMs[19, 60, 61, 63]. The PK parameters indicated relatively small differences after repeated oral doses among different CYP2C19 genotypes, although the mean AUC in PMs was still higher than

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in EMs. The values of AUC and t1/2 in CYP2C19 PMs were higher than those in EMs after a single intravenous administration of lansoprazole[81]. In addition, intravenous formulations of lansoprazole were observed to exert single- and multiple-dose effects

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on PK/PD properties, similar to those observed after administration with the same

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dose of intact capsules in healthy volunteers[82]. Intravenous lansoprazole is approved in the USA for short-term use (up to 7 days) in patients with erosive

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esophagitis who are temporarily unable to take oral formulations and is still the first

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choice for acute non-variceal gastrointestinal bleeding[83]. In addition, some patients requiring acid-suppression therapy may be unable to take oral medications owing to

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dysphagia. Therefore, lansoprazole injection cannot be replaced by its oral formulation in many cases.

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Lansoprazole is a racemic mixture of its S- and R-enantiomers; dexlansoprazole

is the R-enantiomer of lansoprazole. As with lansoprazole[30, 61], the PK/PD parameters of dexlansoprazole[7] are also significantly affected by CYP2C19 polymorphism. Our previous study demonstrated that the mean AUC had ratios of 1.00, 1.85, and 3.95 in homEMs, hetEMs, and PMs, respectively, after a single 14

intravenous administration (30 mg) of dexlansoprazole; the t1/2 value in PMs was approximately 3.47-fold higher than that in homEM, while PD parameters divided by CYP2C19 genotypes had relatively small differences between homEMs and PMs[7]. In addition, gastric H+,K+-ATPase polymorphisms have a significant influence on the acid-suppression effect of dexlansoprazole. Significant differences between gastric H+,K+-ATPase homozygote and wildtype were found in the Δ (delta)-values (values at pH-t

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baseline subtracted from values after administration) for the mean pH, AUCτ 1-τ 2 , TpH≥3 (%), TpH≥4 (%), and TpH≥6 (%) during 0–4, 14–24, and 0–24 h intervals, whereas PK parameters were not affected by the gastric H+,K+-ATPase genotype.

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Further analysis to compare the PD properties between CYP2C19 and gastric

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H+,K+-ATPase genotypes was undertaken to reveal which genotype had a stronger gastric acid suppression effect. There was no significant difference in acid inhibition

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effect among CYP2C19 homEMs, hetEMs, and PMs during the first 4 h after

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intravenous administration of dexlansoprazole, whereas H+,K+-ATPase homozygotes pH-t

had significantly greater gastric acid-suppression effects for ΔAUCτ 1-τ 2 , ΔTpH≥3(%),

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and ΔTpH≥4(%) than heterozygotes or wildtypes. Even in CYP2C19 EMs, the same results were observed among each group of H+,K+-ATPase genotypes which indicated

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that the gastric H+,K+-ATPase polymorphisms may be one of the major causes of inter-individual differences in efficacy. This provides a partial explanation for why some patients cannot achieve a satisfactory gastric acid-suppression effect after a conventional clinical dose of PPIs[7].

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the CYP isoforms to the metabolic pathway.

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Figure 3. Metabolic pathways of lansoprazole. The thicker the arrow, the larger the contribution of

Pantoprazole

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Pantoprazole, as a traditional PPI and benzimidazole derivative, is used widely in clinical practice for acid inhibition and the treatment of gastroesophageal reflux disease,

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peptic ulcer diseases, and infection with H. pylori[58, 84]. It is mainly metabolized by

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different metabolic enzymes, as shown in Figure 4 (CYP2C19, CYP3A4). The blood concentration of pantoprazole at 3 h post-oral dose was significantly lower in carriers of the CYP2C19*17/*17 genotype than the CYP2C19 wild-type after a single oral dose of pantoprazole (40 mg). Volunteers with the CYP2C19*2/*2 allele showed a 506% increase in AUC and a 572% prolongation in t1/2. The lowest clearance was observed in the carriers of the *2/*2 genotype (3.68 L/h) and the highest clearance in 16

subjects with the *17/*17 genotype (31.13 L/h)[67]. In addition, the 1-year cumulative failure rate of on-demand therapy was significantly higher in homEMs than in hetEMs or PMs after a continuous 40 mg daily oral dose of pantoprazole tablets for patients with severe reflux esophagitis (Los Angeles grade C or D). The mean monthly number of tablets for pantoprazole was higher in homEMs and hetEMs than in PMs (18.6 vs 16.3 vs 11.5, P < 0.05). Sheu et al[85] proposed that the effective shift to on-demand

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therapy was mainly dependent on the CYP2C19 genotype of patients; with reflux

esophagitis, patients with Los Angeles grade C or D showed perfect recovery after

repeated oral dosing of pantoprazole. It has been reported that Cmax and AUC values

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are much higher in PMs than those in homEMs and hetEMs after oral administration

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of pantoprazole[67, 68], although the differences were smaller than those after administration of omeprazole or lansoprazole. Deshpande et al.[68] proposed that

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PMs had the highest AUC, whereas UMs had the lowest AUC on the fifth day after

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oral administration of pantoprazole in Asian individuals. These data were in accordance with the observations made in Caucasians after a single administration of

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pantoprazole[67]. The PK/PD parameters following the intravenous administration of pantoprazole are summarized for different genotypes in Table 3. The 24-h median pH

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was different among various genotypes after a single intravenous dose of pantoprazole, whereas the differences after repeated dosing were relatively small among the different CYP2C19 genotypes[66]. Several previous studies that evaluated whether oral or intravenous pantoprazole was a consistent and long-lasting inhibitor of gastric acid secretion have reported satisfactory results in patients with acid-related 17

diseases[86]. Numerous studies and meta-analyses have confirmed the efficacy of intravenous pantoprazole for the treatment of peptic ulcer bleeding and stress ulcer bleeding[87]. Thus, pantoprazole is now one of the most commonly administered

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intravenous PPIs for the treatment of non-variceal gastrointestinal bleeding.

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Figure 4. Metabolic pathways of pantoprazole. The thicker the arrow, the larger the contribution of the CYP isoforms to the metabolic pathway.

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Rabeprazole

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Rabeprazole, a second-generation PPI, is also a substituted benzimidazole. It provides reliable control of gastric acid secretion, with more powerful antisecretory activity and rapid increases in intragastric pH than first-generation PPIs such as omeprazole and lansoprazole[31, 88, 89]. Rabeprazole has a better acid control and significantly longer duration of intragastric pH>4 in the 24 h post-dose than lansoprazole, omeprazole, or pantoprazole[90]. In addition, night-time pH 18

measurements made on the first dosing day have revealed a superior effect on intragastric pH than that achieved by standard doses of pantoprazole or omeprazole[90]. In our previous research, the AUC ratios of the low- (10 mg), middle- (20 mg), and high-dose (40 mg) groups were 1:1.9:3.6 and 1:1.8:3.4 respectively, after a single intravenous injection of rabeprazole (on Day 1) or after repeated dosing for 5 days[91]. In addition, the high-dose group had the longest pH>4

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and pH>6 holding times, whereas the low-dose group had the shortest holding time. These results indicated that the PK/PD of rabeprazole is concentration-dependent,

with higher 24-h intragastric pH values obtained with higher AUC and Cmax values,

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which was similar to that for other PPIs[7, 92-94]. Rabeprazole has been reported to

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be mainly metabolized (approximately 85%) via a non-enzymatic pathway to thioether-rabeprazole, with only minor involvement of CYP2C19 and CYP3A4[71,

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91]. The thioether-rabeprazole is then further stereoselectively re-oxidized, mainly to

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(R)-rabeprazole. Therefore, the acid-suppressive effect of rabeprazole is considered to be less affected by CYP2C19 genotype-phenotype or genotype status compared with

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other PPIs (Figure 5). In healthy volunteers, the AUC ratio (PMs vs. homEMs) of rabeprazole (20 mg) was reported to be 3.3 after administration of a single oral dose,

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whereas that of omeprazole (20 mg) was 10.7[24]. The AUC ratio (PMs vs. homEMs) was found to be 1.2 after approximately 2 months of oral administration of rabeprazole (20 mg) in patients with gastroesophageal reflux disease[54]. Shimatani et al.[95] reported that the potency of acid inhibition by rabeprazole was slightly influenced by CYP2C19 polymorphisms, whereas Hu et al.[71] demonstrated that the 19

PK properties of rabeprazole were partially dependent on the CYP2C19 genotype and that the acid-suppression efficacy was not significantly influenced by CYP2C19 polymorphisms. These results indicated that the differences in PK/PD parameters were relatively small among homEMs, hetEMs, and PMs after the administration of rabeprazole in healthy volunteers or patients with gastroesophageal reflux disease. In terms of PK parameters, rabeprazole is more applicable for patients with different

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CYP2C19 genotypes. It would therefore be expected that patients treated with

rabeprazole show a more consistent healing efficacy than those receiving other PPIs. In particular, H. pylori eradication is also affected by CYP2C19 polymorphism in

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patients undergoing rabeprazole-based therapies (Table 2). The ratio of H. pylori

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eradication rate (PMs vs. homEMs) was reported to be 1, 1, 0.9, 1.2 and 1.7 in patients receiving rabeprazole-based therapies[40, 44, 45, 48, 49], which was smaller

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than for omeprazole- (1.2, 1.6, 1.4 and 1.4)[39-42], lansoprazole- (1.2 and 1.2)[43, 44]

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or pantoprazole- based therapies (1, 1.4 and 1.4)[45-47]. This may be because rabeprazole is mostly metabolized via a nonenzymatic process, with only minor

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participation of CYP2C19.

20

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Figure 5. Metabolic pathways of rabeprazole. The thicker the arrow, the larger the contribution of

Ilaprazole

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the CYP isoforms to the metabolic pathway.

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Ilaprazole[88] (also called as IY81149), a newly marketed PPI, belongs to the class of substituted benzimidazole molecules, and is chemically related to

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omeprazole[96, 97]. Ilaprazole can elicit a marked and dose-dependent gastric acid suppression effect, together with a longer plasma half-life compared with omeprazole[98]. Shin et al.[99] demonstrated that ilaprazole achieved better intragastric pH control than esomeprazole for the entire 24-h period, whereas esomeprazole provided better intragastric pH control during the initial 4 h. Although 21

most PPIs are mainly metabolized by CYP2C19, CYP3A may have a more critical role in the clearance of ilaprazole than CYP2C19 because ilaprazole sulfone (the major product) and hydroxyl ilaprazole (the minor product) are the two main circulating metabolites in plasma (Figure 6)[100, 101]. In addition, inhibition of CYP3A4 had a significant effect on ilaprazole concentration, whereas the inhibition of CYP2C19 had no significant effect, which also indicated that the metabolism of

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ilaprazole in vivo was mainly related to CYP3A4[100]. In addition, there was no

significant difference in Css, max and AUC0-24 of ilaprazole or ilaprazole sulfone among

different CYP2C19 genotypes after daily oral administration of 10 mg ilaprazole for 7

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days[102]. The mean 24-h intragastric pH, TpH>4 (%), and the AUC0-24 of serum

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gastrin were not significantly different among CYP2C19 genotypes. No serious adverse events were observed during the short-term use (5 days) of ilaprazole[103,

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104], however, research on this topic, especially on the long-term safety, remains

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insufficient.

22

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the CYP isoforms to the metabolic pathway.

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DISCUSSION

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Figure 6. Metabolic pathways of ilaprazole. The thicker the arrow, the larger the contribution of

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Since the first PPI (omeprazole) was marketed, PPIs have gradually replaced histamine 2 receptor antagonists (H2RAs) for the treatment of gastroesophageal reflux

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disease and other acid-related disorders[88]. Several studies have demonstrated an association between polymorphisms of CYP2C19/CYP3A4 and inter-individual

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variability in the disposition and pharmacologic responses of PPIs[105-107]. Among the main PPIs, the various influences of the CYP2C19 polymorphisms on metabolic parameters are different (omeprazole > lansoprazole > pantoprazole > rabeprazole > ilaprazole). The greatest impact was on omeprazole, which showed the largest differences in PK/PD properties and clinical efficacy among different CYP2C19 23

genotypes, whereas the S-isomer of omeprazole (esomeprazole) was less sensitive to CYP2C19 polymorphism, resulting in more stable plasma concentrations among the different CYP2C19 genotypes[108]. These data were in accordance with the observations made for lansopraozle. PPIs are unstable in an acidic environment; thus, oral dosage forms are usually formulated as enteric preparations to prevent their early conversion in stomach[109].

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The absorption of PPIs after oral administration is affected by formulation type, diet, gastrointestinal physiology, and various other factors, which will influence the PK parameters of PPIs[110]. In contrast, intravenous preparations are less affected by

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these factors[7], and have relatively small individual differences in PK/PD values.

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The approved dose of omeprazole in Japan is 20 mg or lower, but 40 mg in most western countries. Asian populations (e.g., Japanese and Chinese populations) have a

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higher proportion of PMs relative to Caucasian and African populations[12, 13], and

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strong gastric acid-suppression can be obtained even with low doses of PPIs. As a non-enzymatic metabolized PPI, rabeprazole has smaller differences in PK/PD

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parameters and acid-suppression effect among the different CYP2C19 genotypes[31, 54]. However, few studies have investigated the effect of CYP2C19 polymorphism on

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rabeprazole injection. Thus, it is difficult to compare the effect of CYP2C19 polymorphism on the PK/PD parameters of rabeprazole between oral and intravenous preparations. In addition, the disposition of PPIs is known to be time- and dose-dependent, with the PK parameters following repeated dosing different from those following a single dose[111]. In particular, single nucleotide polymorphisms 24

(SNPs) of the gastric H+,K+-ATPase α-subunit may be correlated with the configuration of the gastric H+,K+-ATPase, and may be related to the differences in individual gastric acid inhibition by PPIs[6]. However, few studies on this topic have been published and clinical studies are needed for confirmation. In contrast, even within the the same genotype, it is necessary to choose the appropriate PPI and dosage. Owing to the effect of the CYP2C19 genotype on H.

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pylori eradication, it is important to identify and optimize an appropriate treatment

strategy, as the standard dosage may achieve poor eradication efficacy in homEMs or UMs[112]. Although a high dose of PPIs can slightly increase the therapeutic

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effect[113], selection of the correct drug appears to be a more reliable approach, as

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double doses of rabeprazole or esomeprazole may increase the eradication rate of H. pylori by 8%–12% compared with first-generation PPIs[114]. This may be due to the

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small inter-individual variation of rabeprazole or esomeprazole metabolism[115]. In

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particular, the metabolism of PPIs in vivo is not only dependent on genotype, but also closely related to the phenoconversion of CYP2C19 enzyme activity, which has a

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direct effect on the clinical efficacy of PPIs[116, 117]. Klieber et al.[116] found that the genotype-phenotype discordance increased by 28% after the administration of

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omeprazole/esomeprazole (EM subjects converted to the PM phenotype), which is in accordance with the accumulation effect in PK parameters after repeated dosing of omeprazole observed in our previous research[16]. These results indicated that the identification of phenoconversion is also important for personalization of therapy after the administration of PPIs. Although few published studies evaluated the 25

phenoconversion of CYP2C19 after PPI administration, this may be an important direction for precision medicine. Based on these findings, genotype detection (gastric H+,K+-ATPase rs2733743 and CYP2C19) and phenoconversion identification could be helpful in determining the optimal dose of PPIs to avoid treatment failure and PPI-related side effects in patients This review has considered many studies of the effects of CYP2C19 and gastric

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H+,K+-ATPase polymorphisms on the PK, PD, and clinical efficacy of PPIs,

encompassing both racemates and individual enantiomers. The main conclusions can

be summarized as follows: (1) Among the main PPIs, rabeprazole and ilaprazole have

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relatively small differences in PK/PD properties and clinical efficacy among different

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CYP2C19 genotypes; (2) enantiomers may have less variation among different CYP2C19 genotypes than racemates after administration at the same dose; (3)

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compared with oral administration, intravenous doses have relatively smaller

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differences among different CYP2C19 genotypes; and (4) gastric H+,K+-ATPase rs2733743 polymorphisms may have a greater effect than CYP2C19 polymorphisms

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on gastric acid-suppression efficiency (as has been confirmed with dexlansoprazole injection). It is necessary for physicians to personalize PPI regimens according to

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each patient’s CYP2C19 and gastric H+,K+-ATPase genotype. Esomeprazole and rabeprazole are preferred in CYP2C19 homEMs and UMs, and the first dose should be doubled while follow-up treatment (regular dose) only needs to ensure an inhibitory effect on the subsequent activation of new pumps. A conventional dose of PPIs can achieve satisfactory inhibition in CYP2C19 hetEMs and PMs. A 26

dose-adjustment of regimens based on the gastric H+,K+-ATPase genotype may also increase the success rate of acid suppression therapy. However, research in this area is relatively rare and further clinical studies are required to determine the correct dose-adjustment protocol.

Confilct of Interest Statement

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conflict of interest in connection with the work submitted.

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We declare that we have no commercial or associative interest that represents a

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Acknowledgements This project was supported by the grants from the National

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Natural Sciences Foundation of China (81673515, 81870436, 81503160), Natural Science Foundation of Jiangsu Province (BK20161591), Six Talent Peaks Project in

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Jiangsu Province (2014-YY-001), Jiangsu Provincial Medical Youth Talent (QNRC2016215), Suzhou science and education Youth Project (KJXW2016067),

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Suzhou industrial technology innovation (SYSD2016046), National key Research &

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Development plan of Ministry of Science and Technology of the People’s Republic of China (2018YFC1314900, 2018YFC1314901), the 2016 industry prospecting and common key technology key projects of Jiangsu Province Science and Technology Department (BE2016002-4), the 2017 projects of Jiangsu Provincial Department of Finance (2150510), and the 2016 projects of Nanjing Science Bureau (201608003).

27

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