Pharmacodynamic Modeling of Pantoprazole's Irreversible Effect on Gastric Acid Secretion in Humans and Rats

Ferron, Géraldine M.; McKeand, William; Mayer, Philip

doi:10.1177/00912700122009953

Cited by 27 publications

(23 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In other experiments, the halftime of restoration of acid secretion in omeprazole-treated rats was 20 h [19,70]. An analysis of the rate of restoration of acid secretion in man after omeprazole inhibition suggested that the halftime was 24 h, whereas after pantoprazole, it was 46 h [12]. Apparently, only the latter drug gave a rate of recovery compatible with restoration of acid secretion as due entirely to pump turnover [9,23].…”

Section: Biology Of Proton Pump Inhibitorsmentioning

confidence: 95%

The gastric HK-ATPase: structure, function, and inhibition

Shin

Munson

Vagin

et al. 2008

Pflugers Arch - Eur J Physiol

220

181

View full text Add to dashboard Cite

The gastric H,K-ATPase, a member of the P 2 -type ATPase family, is the integral membrane protein responsible for gastric acid secretion. It is an α,β-heterodimeric enzyme that exchanges cytoplasmic hydronium with extracellular potassium. The catalytic α subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of the transmembrane segments TM4, TM5,TM6, and TM8. Comparison to the known structure of the SERCA pump, mutagenesis, and molecular modeling has identified these as constituents of the ion binding domain. The β subunit has one transmembrane segment with N terminus in cytoplasmic region. The extracellular domain of the β subunit contains six or seven Nlinked glycosylation sites. N-glycosylation is important for the enzyme assembly, maturation, and sorting. The enzyme pumps acid by a series of conformational changes from an E 1 (ion site in) to an E 2 (ion site out) configuration following binding of MgATP and phosphorylation. Several experimental observations support the hypothesis that expulsion of the proton at 160 mM (pH 0.8) results from movement of lysine 791 into the ion binding site in the E 2 P configuration. Potassium access from the lumen depends on activation of a K and Cl conductance via a KCNQ1/KCNE2 complex and Clic6. K movement through the luminal channel in E 2 P is proposed to displace the lysine along with dephosphorylation to return the enzyme to the E 1 configuration. This enzyme is inhibited by the unique proton pump inhibitor class of drug, allowing therapy of acid-related diseases.

show abstract

Section: Biology Of Proton Pump Inhibitorsmentioning

confidence: 95%

The gastric HK-ATPase: structure, function, and inhibition

Shin

Munson

Vagin

et al. 2008

Pflugers Arch - Eur J Physiol

220

181

View full text Add to dashboard Cite

show abstract

“…The center diagram shows a basic model with zero-order production ( k in ), first-order loss ( k out ), and an irreversible (second-order, k·C p ) inactivation of the response parameter. This type of model has been used to account for the anti-platelet inactivation of COX-1 by aspirin (32) as well as the effects of pantoprazole and other proton pump inhibitors causing reduction in gastric acidity (33). …”

Section: Diversity Of Basic Turnover Modelsmentioning

confidence: 99%

Moving from Basic Toward Systems Pharmacodynamic Models

Jusko

2013

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

Building upon many classical foundations of pharmacology, a diverse array of mechanistic pharmacokinetic-pharmacodynamic (PK/PD) models have emerged based on mechanisms of drug action and primary rate-limiting or turnover processes in physiology. An array of basic models can be extended to handle various complexities including tolerance and can readily be employed as building blocks in assembling enhanced PK/PD or small systems models. Our corticosteroid models demonstrate these concepts as well as elements of horizontal and vertical integration of molecular to whole-body processes. The potential advantages and challenges in moving PK/PD towards systems models are described.

show abstract

“…The study group received subcutaneous pantoprazole (Wyeth Pharmaceuticals Inc., Philadelphia, PA) at a dose of 5 mg/kg injected subcutaneously under the neck fur every 8 h for 3 days and 1 h before the procedure. Standard PPI doses for rats vary in the literature between 5 to 20 mg/kg [4,5]. The current dose was chosen to obtain noticeable change in gastric pH in this rat model.…”

Section: Protocolmentioning

confidence: 99%

The impact of proton-pump inhibitors on intraperitoneal sepsis: a word of caution for transgastric NOTES procedures

et al. 2009

View full text Add to dashboard Cite

Background During transgastric natural orifice transluminal endoscopic surgery (NOTES), there is an iatrogenic perforation of the gastric wall with leakage of gastric contents into the peritoneal cavity. The aim of this study is to determine the effect of proton-pump inhibitors (PPI) and alterations of gastric pH on infection during transgastric surgery. Methods Thirty 250-g male Sprague-Dawley rats were divided into a study group (SG, n = 15) and a control group (CG, n =15). SG were given 5 mg/kg pantoprazole for 3 days before procedure and another dose 1 h before. CG received saline at similar time points. A mini-laparotomy with gastrotomy was performed. Aspiration of 2.0 cc gastric contents was removed from the stomach and injected into the peritoneal cavity of both groups. Gastric pH and peritoneal pH levels were obtained. Gastric aspirate was sent for culture. White blood cell counts (WBC) were obtained on postoperative days 1, 7, and 14, and C-reactive protein (CRP) levels were obtained on postoperative day 1. At day 14, a necropsy was performed and aerobic and anaerobic cultures of the peritoneal cavity were obtained. Results There were no deaths in either group. The average gastric pH in the SG was 5.13 versus 3.26 (p = 0.03) in the CG. The average peritoneal pH was similar in both groups. The WBC in the SG was 4.5 vs. 3.5 (1,000 cells/ mm) in the CG. There was no elevation in CRP levels in either group. Bacterial cultures were positive in 3/15 (20%) rats in the CG and in 9/15 (60%) in the SG (p = 0.008). Intra-abdominal abscesses were found in 2/15 (13%) rats in the CG and in 5/15 (33%) in the SG (p = 0.08). Conclusions Pretreatment with a PPI resulted in a higher rate of peritoneal bacterial contamination and abscess formation. The acidic environment of the stomach appears to be protective against infection when intraperitoneal contamination occurs as a result of gastrotomy.

show abstract

Pharmacodynamic Modeling of Pantoprazole's Irreversible Effect on Gastric Acid Secretion in Humans and Rats

Cited by 27 publications

References 13 publications

The gastric HK-ATPase: structure, function, and inhibition

The gastric HK-ATPase: structure, function, and inhibition

Moving from Basic Toward Systems Pharmacodynamic Models

The impact of proton-pump inhibitors on intraperitoneal sepsis: a word of caution for transgastric NOTES procedures

Contact Info

Product

Resources

About