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Link to original content: https://pubmed.ncbi.nlm.nih.gov/23350044
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. 2013 Jan;19(1):25-35.
doi: 10.5056/jnm.2013.19.1.25. Epub 2013 Jan 8.

Pharmacokinetics and pharmacodynamics of the proton pump inhibitors

Jai Moo Shin  1 , Nayoung Kim
Affiliations

Pharmacokinetics and pharmacodynamics of the proton pump inhibitors

Jai Moo Shin et al. J Neurogastroenterol Motil. 2013 Jan.

Abstract

Proton pump inhibitor (PPI) is a prodrug which is activated by acid. Activated PPI binds covalently to the gastric H(+), K(+)-ATPase via disulfide bond. Cys813 is the primary site responsible for the inhibition of acid pump enzyme, where PPIs bind. Omeprazole was the first PPI introduced in market, followed by pantoprazole, lansoprazole and rabeprazole. Though these PPIs share the core structures benzimidazole and pyridine, their pharmacokinetics and pharmacodynamics are a little different. Several factors must be considered in understanding the pharmacodynamics of PPIs, including: accumulation of PPI in the parietal cell, the proportion of the pump enzyme located at the canaliculus, de novo synthesis of new pump enzyme, metabolism of PPI, amounts of covalent binding of PPI in the parietal cell, and the stability of PPI binding. PPIs have about 1hour of elimination half-life. Area under the plasmic concentration curve and the intragastric pH profile are very good indicators for evaluating PPI efficacy. Though CYP2C19 and CYP3A4 polymorphism are major components of PPI metabolism, the pharmacokinetics and pharmacodynamics of racemic mixture of PPIs depend on the CYP2C19 genotype status. S-omeprazole is relatively insensitive to CYP2C19, so better control of the intragastric pH is achieved. Similarly, R-lansoprazole was developed in order to increase the drug activity. Delayed-release formulation resulted in a longer duration of effective concentration of R-lansoprazole in blood, in addition to metabolic advantage. Thus, dexlansoprazole showed best control of the intragastric pH among the present PPIs. Overall, PPIs made significant progress in the management of acid-related diseases and improved health-related quality of life.

Keywords: Area under the plasmic concentration curve; Gastric acid; Gastric endogenous activator protein, mammal; Hydrogen potassium ATPase; Pharmacokinetics; Pharmacology; Proton pump inhibitors.

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Conflict of interest statement

Conflicts of interest: None.

Figures

Figure 1
Figure 1
A model structure of the gastric H+, K+-ATPase. The gastric H+, K+-ATPase α subunit has 3 lobes, N (ATP binding), P (phosphorylation) and A (activation) domains in the cytoplasmic domain, and 3 transmembrane segments in the membrane domain. The gastric β subunit has short cytoplasmic region, 1 transmembrane segment, and a heavily glycosylated extracellular region. The number of Asn sites having carbohydrates is based on pig H+, K+-ATPase.
Figure 2
Figure 2
The catalytic cycle of the gastric H+, K+-ATPase. A hydronium ion binds to the cytoplasmic surface of the gastric H+, K+-ATPase (E1 form) and ATP phosphorylates the protein at Asp386 to form the first ion transport intermediate in the E1P form. The E1P form then converts by a conformational change to the second ion transport form, E2P, with the ion site now exposed to the exterior and hydronium is released. To this form, K+ binds from the outside surface to the same region from which the hydronium was released, and the enzyme dephosphorylates, and then K+ is trapped within the membrane domain in the occluded form. The K+ is then de-occluded allowing reformation of the E1 form of the enzyme with the ion site now again facing the cytoplasm and K+ is displaced when ATP is bound.
Figure 3
Figure 3
Structures of proton pump inhibitors.
Figure 4
Figure 4
The mechanism of activation of the proton pump inhibitors shown in general structural form. The substituent R1, R2, R3 and R4 of the general structure (Bz-Py) represent a substituent chosen from hydrogen, methoxy, methyl and substituted alkoxy group. Top part shows the protonation of the pyridine ring and the second row of structures shows protonation also of the benzimidazole ring. The bis-protonated forms are in equilibrium with the protonated benzimidazole and unprotonated pyridine. In brackets is shown the mechanism of activation whereby the 2C of the protonated benzimidazole reacts with the unprotonated fraction of the pyridine moiety that results in rearrangement to a permanent cationic tetracyclic sulfenic acid which in aqueous solute dehydrates to form a cationic sulfenamide. Either of these thiophilic species can react with the enzyme to form disulfides with one or more enzyme cysteines accessible from the luminal surface of the enzyme. Adapted from Shin et al.
Figure 5
Figure 5
Comparison of % inhibition, % omeprazole (OMP) binding and % plasma level. Radioactive OMP was orally administrated at a dosage of 10 mg/kg, and the drug concentration in the plasma level and the inhibition of acid secretion in the pylorus-ligated rats were measured. Then, the pump enzyme was isolated from each stomach. Radioactive OMP bound to the enzyme was measured together with quantity of the enzyme. Maximum binding stoichiometry was 2.5 nmol/mg of the enzyme. Error bar is SD (n = 5). % inhibition, % inhibition of gastric acid secretion.
Figure 6
Figure 6
Comparison of dexlansoprazole modified-release (MR) and esomeprazole delayed-release (DR). (A) Mean plasma concentration-time curves of dexlansoprazole and esomeprazole after single oral doses of dexlansoprazole MR 60 mg and esomeprazole 40 mg DR capsule in healthy subjects. (B) Mean intragastric pH from 0 to 24 hours postdose after single oral doses of dexlansoprazole MR 60 mg (open square) and esomeprazole 40 mg DR capsule (closed circle). Adapted from Kukulka et al.
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