Luning Sun

A Review of the Novel Application and Potential Adverse Effects of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are known as a class of pharmaceutical agents that target H+/K+-ATPase, which is located in gastric parietal cells. PPIs are widely used in the treatment of gastric acid-related diseases including peptic ulcer disease, erosive esophagitis and gastroesophageal reflux disease, and so on. These drugs present an excellent safety profile and have become one of the most commonly prescribed drugs in primary and specialty care. Except for gastric acid-related diseases, PPIs can also be used in the treatment of Helicobacter pylori infection, viral infections, respiratory system diseases, cancer and so on. Although PPIs are mainly used short term in patients with peptic ulcer disease, nowadays these drugs are increasingly used long term, and frequently for a lifetime, for instance in patients with typical or atypical symptoms of gastroesophageal reflux disease and in NSAID or aspirin users at risk of gastrotoxicity and related complications including hemorrhage, perforation and gastric outlet obstruction. Long-term use of PPIs may lead to potential adverse effects, such as osteoporotic fracture, renal damage, infection (pneumonia and clostridium difficile infection), rhabdomyolysis, nutritional deficiencies (vitamin B12, magnesium and iron), anemia and thrombocytopenia. In this article, we will review some novel uses of PPIs in other fields and summarize the underlying adverse reactions.

Enantioselective determination of (R)‐ and (S)‐lansoprazole in human plasma by chiral liquid chromatography with mass spectrometry and its application to a stereoselective pharmacokinetic study

A simple and enantioselective method was developed and validated for the simultaneous determination of (R)- and (S)-lansoprazole in human plasma by chiral liquid chromatography with tandem mass spectrometry. Lansoprazole enantiomers and internal standard (esomeprazole) were extracted from plasma using acetonitrile as protein precipitating agent. Baseline chiral separation was achieved within 9.0 min on a Chiralpak IC column (150 mm × 4.6 mm, 5 μm) with the column temperature of 30°C. The mobile phase consisted of 10 mM ammonium acetate solution containing 0.05% acetic acid/acetonitrile (50:50, v/v). The mass spectrometric analysis was performed using a QTrap 5500 mass spectrometer coupled with an electrospray ionization source in positive ion mode. The multiple reactions monitoring transitions of m/z 370.1→252.1 and 346.1→198.1 were used to quantify lansoprazole enantiomers and esomeprazole, respectively. For each enantiomer, no apparent matrix effect was found, the calibration curve was linear over 5.00-3000 ng/mL, the intra- and inter-day precisions were below 10.0%, and the accuracy was -3.8 to 3.3%. Analytes were stable during the study. No chiral inversion was observed during sample storage, preparation procedure and analysis. The method was applied to the stereoselective pharmacokinetic studies in human after intravenous administration of dexlansoprazole or racemic lansoprazole.

Hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry method for the simultaneous determination of l-valine, l-leucine, l-isoleucine, l-phenylalanine, and l-tyrosine in human serum.

l-Valine, l-leucine, l-isoleucine, l-phenylalanine, and l-tyrosine are important proposed biomarkers for the early detection and diagnosis of type 2 diabetes. A simple and selective hydrophilic interaction chromatography with tandem mass spectrometry method was developed for the simultaneous determination of these amino acids in human serum, using stable isotope-labeled amino acids as internal standards. Chromatographic separation was carried out on a Syncronis HILIC column (150 mm × 2.1 mm, 5 μm) with the column temperature of 35°C and a mobile phase consisted of acetonitrile/120 mM ammonium acetate (89:11, v/v), and the run time was 11.0 min. The mass spectrometric analysis was performed using a QTRAP 5500 mass spectrometer coupled with an electrospray ionization source in positive ion mode. As these five amino acids are endogenous compounds in serum, we used the corresponding stable isotope-labeled amino acids to evaluate the matrix effect and recovery in serum. The matrix effect was 98.7-107.3%, and the recovery was 92.7-102.3%. Calibration curves spiked unlabeled amino acids in water were linear over the range of 0.200-100 μg/mL. The accuracy, inter-, and intraday precision were below 10.2%. Analytes were stable during the study. This assay method has been validated and applied to the early diagnosis research of type 2 diabetes.

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 quantification of antofloxacin and its major metabolite in human urine by HPLC--MS/MS, and its application to a pharmacokinetic study.

This study presents a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the simultaneous determination of antofloxacinin and its main metabolite - N-demethylated metabolite (N-DM) - in human urine. Ornidazole was used as the internal standard. This was a clinical urine recovery study, in which 10 healthy Chinese volunteers were intravenously administered a single 200 mg dose of antofloxacin hydrochloride. Compounds were extracted by albumen precipitation, after which samples were isocratically eluted using a Poroshell 120 SB-C18 column, and were analysed using HPLC-MS/MS under electronic spray ionization positive ion mode. The method was successfully applied in a urine pharmacokinetic study of antofloxacinin, with a detection range of 0.02/0.01 to 200/100 μg/mL (for antofioxacin/N-DM).The average percentages of antofioxacin/N-DM measured in urinary excretion frp, 10 volunteers were 54.9 ± 5.7/8.2 ± 2.5% in 120 h duration.

Genetic Polymorphism on the Pharmacokinetics and Pharmacodynamics of Platelet-derived Growth Factor Receptor (PDGFR) Kinase Inhibitors

BACKGROUND Platelet-derived Growth Factor Receptor (PDGFR) is a kind of Receptor Tyrosine Kinases (RTKs). PDGFR Tyrosine Kinase Inhibitors (TKIs) which are small molecule inhibitors targeting PDGFR prevent and block cell proliferation signal transduction pathways. Recently, there have been 11 TKIs (including imatinib, sunitinib, regorafenib, sorafenib, pazopanib, axitinib, dasatinib, nilotinib, lenvatinib, cabozantinib and ponatinib) targeting PDGFR approved by FDA for the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors, renal cell carcinoma et al. Pharmacokinetics (PK) reflects the processes of drugs in body, while pharmacodynamics (PD) reflects the efficacy. Genetic polymorphisms of metabolizers and transporters contribute to highly inter-individual variability in PK and PD. This review aims to introduce the clinical applications, instruction and usage, PK, PD and pharmacogenetics of these PDGFR TKIs. METHODS In vivo and in vitro studies about PDGFR TKIs were searched from PubMed. Data and information were analyzed and summarized. RESULTS The overview of (1) general information on PDGFR kinase inhibitors; (2) PK parameters of PDGFR kinase inhibitors; (3) metabolic enzymes and transporters of PDGFR kinase inhibitors; (4) main drug interactions of PDGFR kinase inhibitors; (5) adverse events of PDGFR kinase inhibitors; and (6) genetic polymorphism on PK and PD of PDGFR kinase inhibitors, was exhibited and discussed in this review. CONCLUSION This review summarized the general information, PK, metabolic enzymes and transporters, main drug interactions, adverse events and pharmacogenetics of FDA approved PDGFR TKIs. Studies showed that Single nucleotide polymorphisms of metabolic enzymes and transporters had influence on the PK and PD of PDGFR TKIs.

Pharmacokinetics and tissue distribution study of clevidipine and its primary metabolite H152/81 in rats.

This present study was designed to investigate the pharmacokinetic profiles and tissue distribution characteristics of clevidipine and its primary metabolite H152/81 in rats following a single intravenous administration of clevidipine butyrate injectable emulsion. For this study, a sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established and validated for the simultaneous quantitation of clevidipine and H152/81 in rat whole blood and various tissues. A Hedera ODS-2 column with two gradient elution programs was employed for the troubleshooting of matrix effect on the detection of analytes among different biological samples. The experimental data showed that clevidipine represented quick elimination from blood with a half-life of about 4.3 min and rapid distribution in all of the investigated tissues after administration; the highest concentration of clevidipine was found in the heart whereas the lowest concentration was detected in the liver. In addition, clevidipine was almost undetectable in most tissues except for heart and brain at 90 min post-dosing, suggesting that there was no apparent long-term accumulation in rat tissues. For H152/81, the peak concentration of 3714 ± 319 ng/mL occurred at 0.129 ± 0.048 h, the half-life was 10.08 ± 1.45 h and area under the concentration-time curve was 42091 ± 3812 ng h/mL after drug administration. In addition, H152/81 was found at significant concentration levels in all tissues, in descending order of lung, kidney, heart, liver, spleen and brain at each time point. The results of current study offer useful clues for better understanding the distribution and metabolism of clevidipine butyrate injectable emulsion in vivo.

Impact of Gastric H+/K+-ATPase rs2733743 on the Intragastric pH-Values of Dexlansoprazole Injection in Chinese Subjects

Background: Not all patients with acid-related disorders receiving proton pump inhibitor (PP) treatment get adequate gastric pH control. The genetic variation of receptors, metabolic enzymes, and transporters are known to cause failures of therapies. We have conducted a study to evaluate the influence of gastric H+/K+-ATPase, CYP2C19, and ABCB1 polymorphisms on the pharmacokinetic and pharmacodynamic profiles of dexlansoprazole injection in healthy Chinese subjects. Methods: A total of 51 subjects were enrolled for pharmacokinetic and pharmacodynamic study after a single intravenous administration of 20 or 30 mg dexlansoprazole. Plasma concentrations were determined using a chiral liquid chromatography-mass spectrometry method. The intragastric pH and baseline-adjusted intragastric pH parameters were introduced to evaluate the pharmacodynamic characters. Genotyping was performed by polymerase chain reaction. Results: The pharmacokinetic parameters were significantly influenced by CYP2C19 phenotypes, and gastric acid secretion inhibition were affected by both gastric H+/K+-ATPase and CYP2C19 polymorphisms. Gastric H+/K+-ATPase genotypes had greater effects than CYP2C19 genotypes on the suppression of gastric acid secretion. Conclusion: Gastric H+/K+-ATPase polymorphism may be one of the main reasons that cause insufficient gastric acid inhibition.