A chiral LC-MS/MS method for the enantioselective determination of R-(+)- and S-(-)-pantoprazole in human plasma and its application to a pharmacokinetic study of S-(-)-pantoprazole sodium injection.

Pantoprazole, a proton pump inhibitor, is clinically used for the treatment of peptic diseases. An enantioselective LC-MS/MS method was developed and validated for the simultaneous determination of pantoprazole enantiomers in human plasma. Pantoprazole enantiomers and the internal standard were extracted from plasma using acetonitrile. Chiral separation was carried on a Chiralpak IE column using the mobile phase consisted of 10 mm ammonium acetate solution containing 0.1% acetic acid-acetonitrile (28 : 72, v/v). MS analysis was performed on an API 4000 mass spectrometer. Multiple reactions monitoring transitions of m/z 384.1→200.1 and 390.1→206.0 were used to quantify pantoprazole enantiomers and internal standard, respectively. For each enantiomer, no apparent matrix effect was found, the calibration curve was linear over 5.00-10,000 ng/mL, the intra- and inter-day precisions were below 10.0%, and the accuracy was within the range of -5.6% to 0.6%. This method was applied to the stereoselective pharmacokinetic studies in human after intravenous administration of S-(-)-pantoprazole sodium injections. No chiral inversion was observed during sample storage, preparation procedure and analysis. While R-(+)-pantoprazole was detected in human plasma with a slightly high concentration, which implied that S-(-)-pantoprazole may convert to R-(+)-pantoprazole in some subjects.

Simultaneous voltammetric analysis of anti-ulcer and D2-antagonist agents in binary mixture using redox sensor and their determination in human serum.

Pencil graphite electrode was successfully modified with a thin film of poly (eriochrome black T) and applied for the sensitive and selective voltammetric simultaneous determination of pantoprazole sodium and domperidone in a binary mixture. The preparation and basic electrochemical behavior of poly (eriochrome black T) film on the Pencil graphite electrode were investigated. The modified electrode has exhibited very high electro-catalytic activity towards the cited mixture. The anodic peaks of the both species were well defined with enhanced oxidation peak currents. Under the optimum conditions, the linearity ranges were 0.4-55×10-7M and 0.1-34×10-7M for pantoprazole sodium and domperidone, respectively with detection limits of 0.12×10-7M and 0.04×10-7M for pantoprazole sodium and domperidone, respectively. The proposed sensor has been successfully applied in the analysis of pantoprazole sodium and domperidone in synthetic binary mixtures and human serum.

Development of Solid-Phase Extraction and HPLC Method for Simultaneous Estimation of Ilaprazole and Glimepiride in Rat Plasma: Application to Pharmacokinetic Studies.

A novel, simple and mass spectrometry (MS) compatible high-performance liquid chromatography (HPLC) method is reported for the simultaneous estimation of ilaprazole (ILA) and glimepiride (GLM) in rat plasma. The bio-analytical procedure involves extraction of ILA, GLM and internal standard (IS) from rat plasma with a solid-phase extraction (SPE) process. The chromatographic analysis was performed on Waters-600 system using an isocratic mobile phase comprising methanol:water (80:20 % v/v) with pH of water modified to three using formic acid at a flow rate of 1.0 mL/min and Kinetex C18 column maintained at 30 ± 1°C. The signals were monitored using a PDA detector set at 225 nm. IS, ILA and GLM eluted at 2.04, 4.7 and 7.4 min, respectively, and the total run time was 10 min. Method validation was performed as per US Food and Drug Administration guidelines and the results met the acceptance criteria. The calibration curve was linear over a concentration range of 10-600 ng/mL (r2 = 0.999). The intra- and inter-day precisions for ILA and GLM were (%RSD values) in the range of 1.52-9.74 and 1.52-11.76%, respectively, in rat plasma. The method was successfully applied in pharmacokinetic studies followed by oral administration of GLM and ILA in rats.

A new pollen-derived microcarrier for pantoprazole delivery.

Plant-derived carriers have emerged as promising materials for drug encapsulation. Especially, sporopollenin microcapsules extracted from diverse pollen species have been proved to be effective drug carriers due to their biocompatibility, homogeneity in size, resistance to harsh chemical conditions and high thermal stability. Here in this study, sporopollenin microcapsules were isolated successfully from the pollens of a common tree (Corylus avellana, the European hazelnut) and used as a carrier for pantoprazole (PaNa) (a proton pump inhibitor). The drug entrapment efficiency was recorded as 29.81%. SEM micrographs clearly showed the drug was loaded into the microcapsules through the apertures of microcapsule and also some drugs were adsorbed on the surface of microcapsules. FT-IR spectra analysis confirmed the drug loading. Thermogravimetric analysis revealed that thermal stability of PaNa was enhanced by encapsulation. In vitro release studies showed that PaNa-loaded sporopollenin microcapsules exhibited better release performance than the control. C. avellana sporopollenin microcapsules can make an efficient carrier for delivery of PaNa.

Revealing the Mechanistic Pathway of Acid Activation of Proton Pump Inhibitors To Inhibit the Gastric Proton Pump: A DFT Study.

Acid-related gastric diseases are associated with disorder of digestive tract acidification due to the acid secretion by gastric proton pump, H+,K+-ATPase. Omeprazole is one of the persuasive irreversible inhibitor of the proton pump H+,K+-ATPase. However, the reports on the mechanistic pathway of irreversible proton pump inhibitors (PPIs) on the acid activation and formation of disulfide complex are scarce in the literature. We have examined the acid activation PPIs, i.e., timoprazole, S-omeprazole and R-omeprazole using M062X/6-31++G(d,p) in aqueous phase with SMD solvation model. The proton pump inhibitor is a prodrug and activated in the acidic canaliculi of the gastric pump H+,K+-ATPase to sulfenic acid which can either form another acid activate intermediate sulfenamide or a disulfide complex with cysteine amino acid of H+,K+-ATPase. The quantum chemical calculations suggest that the transition state (TS5) for the disulfide complex formation is the rate-determining step of the multistep acid inhibition process by PPIs. The free energy barrier of TS5 is 5.5 kcal/mol higher for timoprazole compared to the S-omeprazole. The stability of the transition state for the formation of disulfide bond between S-omeprazole and cysteine amino acid of H+,K+-ATPase is governed by inter- and intramolecular hydrogen bonding. The disulfide complex for S-omeprazole is thermodynamically more stable by 4.5 kcal/mol in aqueous phase compared to disulfide complex of timoprazole, which corroborates the less efficacy of timoprazole as irreversible PPI for acid inhibition process. It has been speculated that sulfenic acid can either form sulfenamide or a stable disulfide complex with cysteine amino acid residue of H+,K+-ATPase. The M062X/6-31++G(d,p) level of theory calculated results reveal that the formation of tetra cyclic sulfenamide is unfavored by ∼17 kcal/mol for S-omeprazole and 11.5 kcal/mol for timoprazole compared to the disulfide complex formation in each case. The DFT calculations have further shed light on the acid activation process of R- and S-isomers of omeprazole. The calculated results suggest that the efficacy of these isomers lie on their metabolic pathway and excretion from human body.

Stereoselective Pharmacodynamics and Pharmacokinetics of Proton Pump Inhibitors.

BACKGROUND: Proton pump inhibitors (PPIs) are a group of gastric acid suppressing drugs, they work by irreversibly blocking the H+/K+ ATPase. The structure of PPIs is similar. They all have a similar core with a sulphur atom chiral center combined with different substituent groups. In relation to the sulphur atom chiral center, the pharmacodynamics, pharmacokinetics are diverse between the racemates and their stereoisomers. But there are no reviews outlining the stereoselective pharmacodynamics and pharmacokinetics in PPIs. This review aims to compare the differences between the stereoisomers of PPIs in their pharmacodynamics and pharmacokinetics parameters. And exploring the development directions of PPIs at present. METHODS: We undertook a search of PubMed databases for PPI research literature including reviews, clinical studies, letters and books, in recent 20 years. The citied papers were high quality, which were carefully screened by authors using standard tools. The data of the pharmacodynamics and pharmacokinetics parameters were selected from the retrieved papers, then making generalization and summary. RESULTS: Ninety-three papers were included in the review, mainly from East Asia, America and Europe. All these papers involved the reviews of PPIs, the pharmacodynamics studies of PPIs and the pharmacokinetics studies of PPIs. Finally, omeprazole, lansoprazole, pantoprazole, rebeprazole and pantoprazole with their enantiomers were discussed in this paper. CONCLUSION: The findings of this review confirm the differences of pharmacodynamics and pharmacokinetics in the racemates and the stereoisomer of PPIs. Providing longer duration, faster time of onset and better nocturnal gastric acid secretion control are the development directions of new generation PPIs. But, due to debate on the necessity and superiority of these new drugs, more validation studies are needed.

High-Throughput Chiral LC-MS/MS Method Using Overlapping Injection Mode for the Determination of Pantoprazole Enantiomers in Human Plasma with Application to Pharmacokinetic Study.

A sensitive and high-throughput chiral liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of R-pantoprazole and S-pantoprazole in human plasma. Sample extraction was carried out by using ethyl acetate liquid-liquid extraction in 96-well plate format. The separation of pantoprazole enantiomers was performed on a CHIRALCEL OJ-RH column and an overlapping injection mode was used to achieve a run time of 5.0 min/sample. The mobile phase consisted of 1) 10 mM ammonium acetate in methanol: acetonitrile (1:1, v/v) and 2) 20 mM ammonium acetate in water. Isocratic elution was used with flow rate at 500 µL/min. The enantiomers were quantified on a triple-quadrupole mass spectrometer under multiple reaction monitoring (MRM) mode with m/z 382.1/230.0 for pantoprazole and m/z 388.4/230.1 for pantoprazole-d7. Linearity from 20.0 to 5000 ng/mL was established for each enantiomer (r(2)  > 0.99). Extraction recovery ranged from 91.7% to 96.4% for R-pantoprazole and from 92.5% to 96.5% for S-pantoprazole and the IS-normalized matrix factor was 0.98 to 1.07 for R-pantoprazole and S-pantoprazole, respectively. The method was demonstrated with acceptable accuracy, precision, selectivity, and stability and the method was applied to support a pharmacokinetic study of a phase I clinical trial of racemic pantoprazole in healthy Chinese subjects. Chirality 28:569-575, 2016. © 2016 Wiley Periodicals, Inc.

In vitro study of the variable effects of proton pump inhibitors on voriconazole.

Voriconazole is a broad-spectrum antifungal agent used for the treatment of severe fungal infections. Maintaining therapeutic concentrations of 1 to 5.5 µg/ml is currently recommended to maximize the exposure-response relationship of voriconazole. However, this is challenging, given the highly variable pharmacokinetics of the drug, which includes metabolism by cytochrome P450 (CYP450) isotypes CYP2C19, CYP3A4, and CYP2C9, through which common metabolic pathways for many medications take place and which are also expressed in different isoforms with various metabolic efficacies. Proton pump inhibitors (PPIs) are also metabolized through these enzymes, making them competitive inhibitors of voriconazole metabolism, and coadministration with voriconazole has been reported to increase total voriconazole exposure. We examined the effects of five PPIs (rabeprazole, pantoprazole, lansoprazole, omeprazole, and esomeprazole) on voriconazole concentrations using four sets of human liver microsomes (HLMs) of different CYP450 phenotypes. Overall, the use of voriconazole in combination with any PPI led to a significantly higher voriconazole yield compared to that achieved with voriconazole alone in both pooled HLMs (77% versus 59%; P < 0.001) and individual HLMs (86% versus 76%; P < 0.001). The mean percent change in the voriconazole yield from that at the baseline after PPI exposure in pooled microsomes ranged from 22% with pantoprazole to 51% with esomeprazole. Future studies are warranted to confirm whether and how the deliberate coadministration of voriconazole and PPIs can be used to boost voriconazole levels in patients with difficult-to-treat fungal infections.

Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole.

The complete vibrational assignment and analysis of the fundamental modes of pantoprazole (PPZ) was carried out using the experimental FT-IR, FT-Raman and UV-Vis data and quantum chemical studies. The observed vibrational data were compared with the wavenumbers derived theoretically for the optimized geometry of the compound from the DFT-B3LYP gradient calculations employing 6-31G (d, p) basis set. Thermodynamic properties like entropy, heat capacity and enthalpy have been calculated for the molecule. HOMO-LUMO energy gap has been calculated. The intramolecular contacts have been interpreted using natural bond orbital (NBO) and natural localized molecular orbital (NLMO) analysis. Important non-linear properties such as electric dipole moment and first hyperpolarizability of PPZ have been computed using B3LYP quantum chemical calculation. Finally, the Mulliken population analysis on atomic charges of the title compound has been calculated.

Optimization and validation of a novel CE method for the enantioseparation of pantoprazole and related benzimididazole using a dual chiral selector system.

A novel CE method was successfully applied to the enantioseparation of pantoprazole and related benzimidazoles, such as tenatoprazole, lansoprazole, and omeprazole. The chiral resolution was performed in an untreated fused-sillica capillary using a dual chiral selector system consisting of copper (II)-l-histidine (l-His) complex and hydroxypropyl-ß-CD. The primary factors affecting its separation efficiency, such as chiral selector, buffer pH, and applied voltage, were optimized. The best results were obtained by using a buffer consisting of 20 mg/mL hydroxypropyl-ß-CD, 10 mmol/L copper(II) acetate, 15 mmol/L l-histidine, 5.0 mmol/L phosphate adjusted to pH 5.0, and 15 kV applied voltage. The enantiomers of all compounds were fully resolved within 20 min with high resolutions of 3.9 to 6.2. The optimized method was extensively validated for determination of the R-(+)-enantiomer impurity in S-(-)-pantoprazole. The LOD and LOQ for the R-(+)-enantiomer were 1.0 and 2.5 µg/mL, respectively. A good linear relationship was obtained in the concentration range of 2.5-25 µg/mL with r(2 ) 0.999 for the R-(+)-enantiomer. The percentage recovery of the R-(+)-enantiomer ranged from 91.6 to 101.3. The method is capable of determining a minimum limit of 0.1% w/w of R-(+)-enantiomer in S-(-)-pantoprazole bulk samples.

Paradoxically augmented anti-tumorigenic action of proton pump inhibitor and GastrininAPCMin/+ intestinal polyposis model.

Though long-term administration of proton pump inhibitor (PPI) imposed the risk of gastrointestinal track tumorigenesis by accompanied hypergastrinemia, no overt increases of colon cancer risk were witnessed after a long-term cohort study. Our recent investigation revealed that PPI prevented colitis-associated carcinogenesis through anti-inflammatory, anti-oxidative, and anti-mutagenic mechanisms in spite of hypergastrinemia. Therefore, we hypothesized that PPI might either antagonize the trophic action of gastrin on gastrointestinal tumorigenesis or synergize to exert augmented anti-tumorigenic actions. We challenged APCMin/+ mice with gastrin, PPI, PPI and gastrin together for 10 weeks and counted intestinal polyposis accompanied with molecular changes. Gastrin significantly increased intestinal polyposis, but combination of PPI and gastrin markedly attenuated intestinal polyposis compared to gastrin-promoted APCMin/+ mice (P<.001), in which significant ß-catenin phosphorylation and inhibition of ß-catenin nuclear translocation were observed with PPI alone or combination of PPI and gastrin, whereas gastrin treatment significantly increased ß-catenin nuclear translocation. Significant footprints of apoptosis, G0/G1 accumulation, inactivation of p38 and extracellular signal-regulated kinase, decreased expressions of CD31, and inhibition of tumor necrosis factor-α and cyclooxygenase-2 were noted in the combination group. In vitro investigations were similar to in vivo findings as shown that PPI treatment inhibited the binding of gastrin to its receptor, inactivated ß-catenin-associated signaling including Tcf/Lef and glycogen synthase kinase ß, and paradoxically inhibited ß-catenin-associated proliferative activities. Our investigations explain why colon cancer risk has not increased despite long-term use of PPIs and provide a rationale for using PPI to achieve anti-tumorigenesis beyond acid suppression.

Identification of proton-pump inhibitor drugs that inhibit Trichomonas vaginalis uridine nucleoside ribohydrolase.

Trichomonas vaginalis continues to be a major health problem with drug-resistant strains increasing in prevalence. Novel antitrichomonal agents that are mechanistically distinct from current therapies are needed. The NIH Clinical Compound Collection was screened to find inhibitors of the uridine ribohydrolase enzyme required by the parasite to scavenge uracil for its growth. The proton-pump inhibitors omeprazole, pantoprazole, and rabeprazole were identified as inhibitors of this enzyme, with IC50 values ranging from 0.3 to 14.5 µM. This suggests a molecular mechanism for the in vitro antitrichomonal activity of these proton-pump inhibitors, and may provide important insights toward structure-based drug design.

Normal and polar-organic-phase high-performance liquid chromatographic enantioresolution of omeprazole, rabeprazole, lansoprazole and pantoprazole using monochloro-methylated cellulose-based chiral stationary phase and determination of dexrabeprazole.

Enantioresolution of four anti-ulcer drugs (chiral sulfoxides), namely, omeprazole, rabeprazole, lansoprazole and pantoprazole, was carried out by high-performance liquid chromatography using a polysaccharide-based chiral stationary phase consisting of monochloromethylated cellulose (Lux cellulose-2) under normal and polar-organic-phase conditions with ultraviolet detection at 285 nm. The method was validated for linearity, accuracy, precision, robustness and limit of detection. The optimized enantioresolution method was compared for both the elution modes. The optimized method was further utilized to check the enantiomeric purity of dexrabeprazole.

The stereoselectivity of CYP2C19 on R- and S-isomers of proton pump inhibitors.

PPIs are mainly metabolized by CYP2C19. It has a stereoselectivity effect on R- and S-isomers of PPIs according to previous studies. However, no study has been reported to elucidate the binding mechanism at the atomic level based on the CYP2C19 crystal structure. Recently, the advent of the first crystal structure of CYP2C19 allowed us to take in silico approaches including MD simulation, MM/GBSA calculation, energy decomposition, and alanine scanning to explore the stereoselectivity of CYP2C19 on R- and S-isomers of PPIs. The key residues responsible for the selective binding for R- and S-isomers of omeprazole, lansoprazole, and pantoprazole are disclosed by free energy and alanine scanning analysis. Structural analysis showed that chiral isomers of PPIs alter their conformations to have strong binding affinities with CYP2C19. Furthermore, a theoretical pharmacophore model of PPIs was obtained with the importance of pharmacophore feature being weighted, basing on our results. Our results are valuable for designing and synthesizing new generation of PPIs in the future.

Efficacy, safety, and tolerability of pantoprazole magnesium in the treatment of reflux symptoms in patients with gastroesophageal reflux disease (GERD): a prospective, multicenter, post-marketing observational study.

BACKGROUND: To improve proton pump inhibitor effects, pharmacological modifications have been developed such as the use of enantiomer molecules (e.g., S-omeprazole, S-pantoprazole, or dexlansoprazole), or addition of NaHCO3 (for an immediate release) or magnesium (with a lower absorption for a more sustained effect). OBJECTIVE: The objective of this study was to assess the efficacy, safety, and tolerability of pantoprazole magnesium 40 mg once daily for 4 weeks, on the relief of reflux symptoms in gastroesophageal reflux disease (GERD) patients. METHODS: A phase IV, open-label, prospective, multicenter study was designed. Patients included were prescribed pantoprazole magnesium 40 mg orally once daily for 28±2 days. All patients had a history of persistent or recurrent heartburn and/or acid regurgitation for at least 3 months. Effectiveness and tolerability data obtained from patients who completed a minimum of 4 weeks of pantoprazole magnesium treatment were considered for analysis. RESULTS: The account of baseline characteristics and demographics of GERD symptom intensity was made by analyzing the group of 4,343 patients that fulfilled all inclusion criteria; 54% were females (n=2,345) and 46% (n=1,998) males, with a mean age of 36.2±7.5 years. Severity of symptoms, assessed by the physician using the 4-point Likert scale, reduced by at least 80% from baseline intensity after treatment in the per protocol population. In the case of the intention-to-treat population, the improvement in symptom intensity was 73%. The number of patients that experienced any adverse events was 175/5,027 (3.48%). CONCLUSIONS: Pantoprazole magnesium is a safe, effective, and well-tolerated drug that significantly improves GERD symptoms.

Reaction of proton pump inhibitors with model peptides results in novel products.

The proposed mechanism for proton pump inhibitors (PPIs) is that PPIs are activated at low pH to the sulfenamide form, which reacts with the sulfhydryl group of cysteine(s) at the active site of the proton pump, to produce reducible disulfide-bonded PPI-proton pump conjugates. However, this mechanism cannot explain the observations that some PPI-protein conjugates are irreducible. This study was designed to investigate the chemistry of the irreducible conjugates by mass spectrometry, using three PPIs and 17 cysteine-containing peptides. While some peptides favored the formation of reducible PPI-peptide adduct, the other peptides mainly produced irreducible adducts. Characterization of the irreducible adduct revealed that the irreducible bonding required the participation of both a sulfhydryl group and a nearby primary amino group. High resolution mass spectrometry suggested a molecular structure of the irreducible adduct. These results suggested a reaction mechanism in which the PPI pyridone form reacted with an amino group and a sulfhydryl group to form an irreducible adduct. The irreducible adduct becomes the dominant product over time because of the irreversible nature of the pyridone-mediated reaction. These findings may explain the irreducible inhibition of H/K-ATPase by PPIs and their relatively slow biological turnover in vivo. [Supplementary materials: available only at http://dx.doi.org/10.1254/jphs.13058FP].

Dissolution improvement of poorly water-soluble drug by cogrinding method using jar mill.

As a representative proton pump inhibitor, Lansoprazole was poorly soluble in water which caused the low oral bioavailability. The present study was carried out to enhance the dissolution of lansoprazole by cogrinding with some commonly used hydrophilic polymers (ß-CD, PVP, HPMC, L-HPC, CS, PEG and PVPP) in the weight ratio of 1:1 for 2 h in the jar mill. Samples of coground mixture, micronised drug, and physical mixture were characterized by XRPD, and DSC, the results showed that the drug crystallinity reduced in the coground process. The amount of drug released from the coground mixtures in PBS (pH 6.8, 37°C) in 30 min was 100% approximately (except the coground mixtures prepared with VPP or PEG) while released from the micronised drug was just about 20%. Increasing the hydrophilicity and diminishing the size of drug particles by cogrinding were the main causes for enhancing the dissolution of the drug. The results of the stability study of lansoprazole in coground mixture showed that there were no significant changes in the drug content and dissolution characteristics 6 months later. It is clear that the cogrinding method described in the article is very effective for enhancing the dissolution of the poorly soluble drugs, and it is easy for industrialization, showing a strong potential for future applications.

Pharmaceutical feasibility of sub-visible particle analysis in parenterals with reduced volume light obscuration methods.

The draft for a new United States Pharmacopoeia (USP) monograph {787} "Sub-visible Particulate Matter in Therapeutic Protein Injections" describes the analysis of sub-visible particles by light obscuration at much lower sample volumes as so far required by the European Pharmacopoeia (Ph. Eur.) and the USP for parenterals in general. Our aim was to show the feasibility of minimizing the sample expenditure required for light obscuration similar to the new USP settings for standards and pharmaceutically relevant samples (both proteins and small molecules), without compromising the data quality. The light obscuration method was downscaled from >20 ml volume as so far specified in Ph. Eur./USP to 1 ml total sample volume. Comparable results for the particle concentration in all tested size classes were obtained with both methods for polystyrene standards, stressed BSA solutions, recombinant human IgG1 formulations, and pantoprazol i.v. solution. An additional advantage of the low volume method is the possibility to detect vial-to-vial variations, which are leveled out when pooling several vials to achieve sufficient volume for the Ph. Eur./USP method. This is in particular important for biotech products where not only the general quality aspect, but also aggregate formation of the drug substance is monitored by light obscuration.

Sustained release enteric coated tablets of pantoprazole: formulation, in vitro and in vivo evaluation.

In this study, an attempt was made to deliver pantoprazole in a sustained manner using delayed release tablets. The tablets were prepared by the wet granulation method using HPMC, cassava starch and polyvinyl pyrrolidine as polymers, Avicel PH 102 (MCC) as filler and potato starch as binder. The prepared tablets were evaluated for hardness, mass variation, friability and drug content uniformity, and the results were found to comply with official standards. The prepared tablets were coated using an enteric coating polymer such as cellulose acetate phthalate, Eudragit L100 and drug coat L100 by the dip coating method. The in vitro release was studied using pH 1.2 acidic buffer and pH 6.8 phosphate buffer and the study revealed that the prepared tablets were able to sustain drug release into the intestine. The anti-ulcer activity was evaluated by a water immersion stress induced ulcer model. The enteric coated pantoprazole tablets significantly reduced ulcer formation.

Synthesis of a DOTA (Gd3+)-conjugate of proton-pump inhibitor pantoprazole for gastric wall imaging studies.

Magnetic resonance imaging (MRI) is used to evaluate gastrointestinal (GI) structure and functions in humans. Despite filling the viscus lumen with a contrast agent, visualization of the viscus wall is limited. To overcome this limitation, we de novo synthesized a conjugate that covalently combines a Gd-based MRI contrast agent, encaged with a chelating agent (DOTA), with pantoprazole, which is a widely used proton pump inhibitor that binds to proton pumps in the stomach and colon. The DOTA linkage was installed at a mechanism-based strategic location in the pantoprazole molecule to minimize a possible negative effect of the structural modification on the drug. It is anticipated that by defining the wall of the stomach and colon, this compound will facilitate functional MRI of the GI tract in humans.