Controlled release floating drug delivery system for proton pump inhibitors lansoprazole: In-vitro, In-vivo floating and pharmacokinetic evaluation.

Lansoprazole (LPZ) show poor bioavailability because of first pass effect and absorption factors. The floating delivery systems could reduce fluctuations in plasma drug concentration through maintaining desirable plasma drug concentration. The objective of present study was to enhance bioavailability despite first pass effect through continuous availability of drug from floating system. Gum tragacanth (GT) and itaconic acid (IA) based floating hydrogels (FH) were synthesized. Parameters optimized were; microwave radiation exposure time, pH, GT:IA ratio and concentration of the glutaraldehyde. Optimized FH were evaluated for entrapment efficiency (% EE), in-vitro release, FTIR, SEM, and in- vitro and in-vivo floating study. Finally, pharmacokinetic was evaluated in ulcer-induced SD rats. Grafting percentage, swelling ratio and %EE of LPZ was 115%, Ì´250% and 90%, respectively. Microwave radiation exposure time, pH of reaction medium, GT:IA ratios and cross linker concentration were 2 min, pH 5, ratios 2:1 and 0.02%, respectively. The optimized FH showed acceptable floating behavior. The X-ray images revealed that hydrogels remained floated over gastric contents up to 24 hours. The in-vitro release and pharmacokinetics revealed availability of LPZ upto to 24h in-vitro and in ulcer-induced SD rats, respectively. The present hydrogels based floating system of lansoprazole is capable to extend the gastric residence time upto 24 hours.

Spectroscopic study of in situ-formed metallocomplexes of proton pump inhibitors in water.

Proton pump inhibitors, such as omeprazole, pantoprazole and lansoprazole, are an important group of clinically used drugs. Generally, they are considered safe without direct toxicity. Nevertheless, their long-term use can be associated with a higher risk of some serious pathological states (e.g. amnesia and oncological and neurodegenerative states). It is well known that dysregulation of the metabolism of transition metals (especially iron ions) plays a significant role in these pathological states and that the above drugs can form complexes with metal ions. However, to the best of our knowledge, this phenomenon has not yet been described in water systems. Therefore, we studied the interaction between these drugs and transition metal ions in the surrounding water environment (water/DMSO, 99:1, v/v) by absorption spectroscopy. In the presence of Fe(III), a strong redshift was observed, and more importantly, the affinities of the drugs (represented as binding constants) were strong enough, especially in the case of omeprazole, so that the formation of a metallocomplex cannot be excluded during the explanation of their side effects.

Inhibition of monoglyceride lipase by proton pump inhibitors: investigation using docking and in vitro experiments.

BACKGROUND: Currently, there is overwhelming evidence linking elevated plasma free fatty acids with insulin resistance and inflammation. Monoglyceride lipase (MGL) plays a crucial metabolic role in lipolysis by mediating the release of fatty acids. Therefore, inhibiting MGL should be a promising pharmacological approach for treating type 2 diabetes and inflammatory disorders. Proton pump inhibitors (PPIs) have been reported to improve glycemic control in type 2 diabetes albeit via largely unknown mechanism. METHODS: The anti-MGL bioactivities of three PPIs, namely, lansoprazole, rabeprazole, and pantoprazole, were investigated using docking experiments and in vitro bioassay. RESULTS: The three PPIs inhibited MGL in low micromolar range with rabeprazole exhibiting the best IC50 at 4.2 µM. Docking experiments showed several binding interactions anchoring PPIs within MGL catalytic site. CONCLUSION: Our study provides evidence for a new mechanism by which PPIs improve insulin sensitivity independent of serum gastrin. The three PPIs effectively inhibit MGL and, therefore, serve as promising leads for the development of new clinical MGL inhibitors.

Development of Dexlansoprazole Delayed-Release Capsules, a Dual Delayed-Release Proton Pump Inhibitor.

Proton pump inhibitors (PPIs) are widely used for treating acid-related disorders. For an "ideal PPI," achieving maximal absorption and sustaining pharmacodynamic effects through the 24-h dosing cycle are critical features. Dexlansoprazole offers a relevant case study on how an improved PPI was developed capitalizing on the rational optimization of a precursor molecule-in this case, using lansoprazole as a starting point, leveraging its chemical properties on pharmacokinetics, and exploring optimized formulations. Dexlansoprazole is the R(+)-enantiomer of lansoprazole and shows stereoselective differences in absorption and metabolism compared with the racemic mixture of lansoprazole. The formulation was further refined to use pulsate-type granules with enteric coating to withstand acidic gastric conditions, while allowing prolonged absorption in the proximal and distal small intestine. As a result, the dual delayed-release formulation of dexlansoprazole has a plasma concentration-time profile characterized by 2 distinct peaks, leading to an extended duration of therapeutic plasma drug concentrations compared with the conventional delayed-release lansoprazole formulation. The dual delayed-release formulation maintains plasma drug concentrations longer than the lansoprazole delayed-release formulation at all doses.

Simultaneous determination of paclitaxel and lansoprazole in rat plasma by LC-MS/MS method and its application to a preclinical pharmacokinetic study of investigational PTX-LAN-PLGA nanoformulation.

In spite of having a remarkable anti tumor activity against a wide variety of cancers, the clinical effectiveness of the major chemotherapeutic drug paclitaxel is often limited by the issues of drug resistance that hampers the therapeutic effectiveness of the drug. The combination of proton pump inhibitor with paclitaxel is an effective approach to overcome therapeutic resistance caused by the acidic microenvironment (Warburg effect) in tumor. In the present study a new simple, precise and selective liquid chromatography tandem mass spectrometry method was developed for quantification of paclitaxel and lansoprazole using esomeprazole as an internal standard and applied for the pharmacokinetic study of investigational paclitaxel - lansoprazole loaded PLGA nanoparticles. The developed method quantifies both the drugs simultaneously irrespective of their dissimilar stability concerns. The detection was exercised with multiple reaction-monitoring mode in positive ionization that yielded highly intense response of parent-product (m/z) transition pair 854.4 → 286.1, 370.1 → 251.9 and 346 → 198 for paclitaxel, lansoprazole and Esomeprazole respectively. The chromatographic separation was achieved using phenomenex Kinetex 5 µ C18 100A 50 × 3.0 mm column and a gradient mobile phase combination of ammonium acetate in deionized water (pH 6.8, 2 mM, w/v) and acetonitrile spiked with formic acid (1:1000, v/v ). This method showed good linearity over a concentration range of 10-320 ng/mL and 100-3200 ng/mL with correlation coefficient (R2) 0.98 and 0.94 for paclitaxel and lansoprazole respectively. Using liquid liquid extraction process both the drugs were extracted from rat plasma. The intra- and inter-day precision and accuracy values were within the variability limits and both the analytes were found to be stable throughout the freeze-thaw, auto-sampler, bench top and long term stability studies. The liquid chromatography tandem mass spectrometry method was successfully validated in accordance with United States Food and Drug administration guidelines and the results were within the acceptable limits. The liquid chromatography tandem mass spectrometry method was successfully utilized for the pharmacokinetic investigation of experimental paclitaxel - lansoprazole loaded PLGA nanoparticles in rat plasma.

Chiral separation of lansoprazole and rabeprazole by capillary electrophoresis using dual cyclodextrin systems.

Novel capillary electrophoresis methods using CDs as chiral selectors were developed and validated for the chiral separation of lansoprazole and rabeprazole, two proton pump inhibitors. Fourteen different neutral and anionic CDs were screened at pH 4 and 7 in the preliminary analysis. Sulfobutyl-ether-ß-CD with a degree of substitution of 6.5 and 10 at neutral pH proved to be the most suitable chiral selector for both compounds. Various dual CD systems were also compared, and the possible mechanisms of enantiomer separation were investigated. A dual selector system containing sulfobutyl-ether-ß-CD degree of substitution 6.5 and native γ-CD proved to be the most adequate system for the separations. Method optimization was carried out using an experimental design approach, performing an initial fractional factorial screening design, followed by a central composite design to establish the optimal analytical conditions. The optimized methods (25 mM phosphate buffer, pH 7, 10 mM sulfobutyl-ether-ß-CD/20 mM γ-CD, +20 kV voltage; 17°C temperature; 50 mbar/3 s injection, detection at 210 nm for lansoprazole; 25 mM phosphate buffer, pH 7, 15 mM sulfobutyl-ether-ß-CD/30 mM γ-CD, +20 kV voltage; 18°C temperature; 50 mbar/3 s injection, detection at 210 nm for rabeprazole) provided baseline separation for lansoprazole (Rs = 2.91) and rabeprazole (Rs = 2.53) enantiomers with favorable migration order (in both cases the S-enantiomers migrates first). The optimized methods were validated according to current guidelines and proved to be reliable, linear, precise, and accurate for the determination of 0.15% distomer as chiral impurity in dexlansoprazole and dexrabeprazole samples.

A Dual Ligand Sol⁻Gel Organic-Silica Hybrid Monolithic Capillary for In-Tube SPME-MS/MS to Determine Amino Acids in Plasma Samples.

This work describes the direct coupling of the in-tube solid-phase microextraction (in-tube SPME) technique to a tandem mass spectrometry system (MS/MS) to determine amino acids (AA) and neurotransmitters (NT) (alanine, serine, isoleucine, leucine, aspartic acid, glutamic acid, lysine, methionine, tyrosine, and tryptophan) in plasma samples from schizophrenic patients. An innovative organic-silica hybrid monolithic capillary with bifunctional groups (amino and cyano) was developed and evaluated as an extraction device for in-tube SPME. The morphological and structural aspects of the monolithic phase were evaluated by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), nitrogen sorption experiments, X-ray diffraction (XRD) analyses, and adsorption experiments. In-tube SPME-MS/MS conditions were established to remove matrix, enrich analytes (monolithic capillary) and improve the sensitivity of the MS/MS system. The proposed method was linear from 45 to 360 ng mL-1 for alanine, from 15 to 300 ng mL-1 for leucine and isoleucine, from 12 to 102 ng mL-1 for methionine, from 10 to 102 ng mL-1 for tyrosine, from 9 to 96 ng mL-1 for tryptophan, from 12 to 210 ng mL-1 for serine, from 12 to 90 ng mL-1 for glutamic acid, from 12 to 102 ng mL-1 for lysine, and from 6 to 36 ng mL-1 for aspartic acid. The precision of intra-assays and inter-assays presented CV values ranged from 1.6% to 14.0%. The accuracy of intra-assays and inter-assays presented RSE values from -11.0% to 13.8%, with the exception of the lower limit of quantification (LLOQ) values. The in-tube SPME-MS/MS method was successfully applied to determine the target AA and NT in plasma samples from schizophrenic patients.

Poly (Octadecyl Methacrylate-Co-Trimethylolpropane Trimethacrylate) Monolithic Column for Hydrophobic in-Tube Solid-Phase Microextraction of Chlorophenoxy Acid Herbicides.

Chlorophenoxy acid herbicides (CAHs), which are widely used on cereal crops, have become an important pollution source in grains. In this work, a highly hydrophobic poly (octadecyl methacrylate-co-trimethylolpropane trimethacrylate) [poly (OMA-co-TRIM)] monolithic column has been specially prepared for hydrophobic in-tube solid-phase microextraction (SPME) of CAHs in rice grains. Due to the hydrophobicity of CAHs in acid conditions, trace CAHs could be efficiently extracted by the prepared monolith with strong hydrophobic interaction. Several factors for online hydrophobic in-tube SPME, including the length of the monolithic column, ACN and trifluoroacetic acid percentage in the sampling solution, elution volume, and elution flow rate, were investigated with respect to the extraction efficiencies of CAHs. Under the optimized conditions, the limits of detection of the four CAHs fell in the range of 0.9-2.1 µg/kg. The calibration curves provided a wide linear range of 5-600 µg/kg and showed good linearity. The recoveries of this method ranged from 87.3% to 111.6%, with relative standard deviations less than 7.3%. Using this novel, highly hydrophobic poly (OMA-co-TRIM) monolith as sorbent, a simple and sensitive online in-tube SPME-HPLC method was proposed for analysis of CAHs residue in practical samples of rice grains.

Inhibition of Gastric H+,K+-ATPase Activity in Vitro by Dissolution Media of Original Brand-Name and Generic Tablets of Lansoprazole, a Proton Pump Inhibitor.

To investigate the inhibitory effect of a commercial proton pump inhibitor (lansoprazole) on the gastric proton pump H+,K+-ATPase in vitro, we used orally disintegrating (OD) tablets including original brand-name and generic tablets. In the course of the development of generic products, dissolution and clinical tests are necessary to ensure their bioequivalence to the original brand-name products; by contrast, there is almost no opportunity to demonstrate their activity in vitro. This study initially compared the similarity of the dissolution of test generic tablets with that of the original brand-name tablets. The dissolution tests for 15 and 30-mg lansoprazole tablets found their dissolution properties were similar. Subsequently, the dissolution media were sampled and then their effects on the H+,K+-ATPase activity were measured using tubulovesicles prepared from the gastric mucosa of hogs. We confirmed that the inhibitory effects of the generic tablets on H+,K+-ATPase activity were consistent with those of the original brand-name tablets. Furthermore, lansoprazole contents in each tablet estimated from their inhibitory effects were in good agreement with their active pharmaceutical ingredient content. To our knowledge, this is the first technical report to compare the in vitro biochemical activity of lansoprazole OD tablets between the original brand-name and generic commercial products.

Stereoselective Inhibition of Renal Basolateral Human Organic Anion Transporter 3 by Lansoprazole Enantiomers.

Lansoprazole, a proton pump inhibitor, potently inhibits human organic anion transporter, hOAT3 (SLC22A8). Lansoprazole has an asymmetric atom in its structure and is clinically administered as a racemic mixture of (R)-and (S)-enantiomers. However, little is known about the stereoselective inhibitory potencies of lansoprazole against hOAT3 and its homolog, hOAT1. In the present study, the stereoselective inhibitory effect of lansoprazole was evaluated using hOAT1-and hOAT3-expressing cultured cells. hOAT1 and hOAT3 transported [14C]p-aminohippurate and [3H]estrone-3-sulfate (ES) with Michaelis-Menten constants of 29.8 ± 4.0 and 30.1 ± 9.0 µmol/L respectively. Lansoprazole enantiomers inhibited hOAT1- and hOAT3-mediated transport of each substrate in a concentration-dependent manner. The IC50 value of (S)-lansoprazole against hOAT3-mediated transport of [3H]ES (0.61 ± 0.08 µmol/L) was significantly lower than that of (R)-lansoprazole (1.75 ± 0.31 µmol/L). In contrast, stereoselectivity was not demonstrated for the inhibition of hOAT1. Furthermore, (S)-lansoprazole inhibited hOAT3-mediated transport of pemetrexed and methotrexate (hOAT3 substrates) more strongly than the corresponding (R)-lansoprazole. This study is the first to demonstrate that the stereoselective inhibitory potency of (S)-lansoprazole against hOAT3 is greater than that of (R)-lansoprazole. The present findings provide novel information about the drug interactions associated with lansoprazole.

Determination of S-(-)-lansoprazole in dexlansoprazole preparation by capillary zone electrophoresis.

Capillary zone electrophoresis was successfully applied to the enantiomeric purity determination of dexlansoprazole using sulfobutyl ether-ß-cyclodextrin and methyl-ß-cyclodextrin as chiral selectors. Separations were carried out in a 50 µm, 64/56 cm fused-silica capillary. The optimized conditions included 90 mM phosphate buffer, pH 6.0, containing 30 mM sulfobutyl ether-ß-cyclodextrin, 20 mM methyl-ß-cyclodextrin as background electrolyte, an applied voltage of 25 kV and a temperature of 16 °C, detection was at 280 nm. The assay was validated for the S-(-)-lansoprazole in the range of 0.2-1.0%. The limit of detection was 0.07%, the limit of quantitation was 0.20%, relative to a total concentration of 4.0 mg mL-1. Intra-day precision varied between 1.72 and 2.07%. Relative standard deviations of inter-day precision ranged between 1.62 and 1.96% for peak area ratio. The assay was applied for the determination of the chiral purity of dexlansoprazole capsules. Recovery in capsules was ranged between 101.7 and 103.1%.

Lansoprazole-sulfide, pharmacokinetics of this promising anti-tuberculous agent.

Lansoprazole (LPZ) is a commercially available proton-pump inhibitor whose primary metabolite, lansoprazole sulfide (LPZS) was recently reported to have in vitro and in vivo activity against Mycobacterium tuberculosis. It was also reported that a 300 mg kg-1 oral administration of LPZS was necessary to reach therapeutic levels in the lung, with the equivalent human dose being unrealistic. A validated liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for the simultaneous quantification LPZ and LPZS in rat plasma and lung homogenates was developed. We administered 15 mg kg-1 oral doses of LPZ to a healthy rat model to determine the pharmacokinetics of its active metabolite, LPZS, in plasma and lung tissue. We found that the LPZS was present in amounts that were below the limit of quantification. This prompted us to administer the same dose of LPZS to the experimental animals intraperitoneally (i.p.). Using this approach, we found high concentrations of LPZS in plasma and lung, 7841.1 and 9761.2 ng mL-1 , respectively, which were significantly greater than the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis. While oral and i.p. administration of LPZ resulted in significant concentrations in the lung, it did not undergo sufficient cellular conversion to its anti-TB metabolite. However, when LPZS itself was administered i.p., significant amounts penetrated the tissue. These results have implications for future in vivo studies exploring the potential of LPZS as an anti-TB compound.

Forced degradation studies of lansoprazole using LC-ESI HRMS and 1 H-NMR experiments: in vitro toxicity evaluation of major degradation products.

Regulatory agencies from all over the world have set up stringent guidelines with regard to drug degradation products due to their toxic effects or carcinogenicity. Lansoprazole, a proton-pump inhibitor, was subjected to forced degradation studies as per ICH guidelines Q1A (R2). The drug was found to degrade under acidic, basic, neutral hydrolysis and oxidative stress conditions, whereas it was found to be stable under thermal and photolytic conditions. The chromatographic separation of the drug and its degradation products were achieved on a Hiber Purospher, C18 (250 × 4.6 mm, 5 µ) column using 10 mM ammonium acetate and acetonitrile as a mobile phase in a gradient elution mode at a flow rate of 1.0 ml/min. The eight degradation products (DP1-8) were identified and characterized by UPLC/ESI/HRMS with in-source CID experiments combined with accurate mass measurements. DP-1, DP-2 and DP-3 were formed in acidic, DP-4 in basic, DP-5 in neutral and DP-1, DP-6, DP-7 and DP-8 were in oxidation stress condition Among eight degradation products, five were hitherto unknown degradation products. In addition, one of the major degradation products, DP-2, was isolated by using semi preparative HPLC and other two, DP-6 and DP-7 were synthesized. The cytotoxic effect of these degradation products (DP-2, DP-6 and DP-7) were tested on normal human cells such as HEK 293 (embryonic kidney cells) and RWPE-1(normal prostate epithelial cells) by MTT assay. From the results of cytotoxicity, it was found that lansoprazole as well as its degradation products (DP-2, DP-6 and DP-7) were nontoxic up to 50-µM concentrations, and the latter showed slightly higher cytotoxicity when compared with that of lansoprazole. DNA binding studies using spectroscopic techniques indicate that DP-2, DP-6 and DP-7 molecules interact with ctDNA and may bind to its surface. Copyright © 2017 John Wiley & Sons, Ltd.

Formulation and Optimization of Lansoprazole Pellets Using Factorial Design Prepared by Extrusion-Spheronization Technique Using Carboxymethyl Tamarind Kernel Powder.

BACKGROUND: In the present study, Lansoprazole pellets were prepared employing a novel excipient Carboxymethyl tamarind kernel powder (CMTKP) using extrusion-spheronization technique. Various research studies including patents have been carried out on this polymer. Pellet formulation was optimized for formulation parameters (concentration of microcrystalline cellulose, CMTKP, croscarmellose sodium and isopropyl alcohol). METHODS: Process parameters (speed and duration of spheronization) were optimized using factorial design. The pellets were evaluated for yield, bulk and tapped density, particle size, hardness, drug content, disintegration time and drug release. RESULTS: The optimized batch showed 93.53% yield, 0.307 kg/cm2 hardness, 2.15 mm average particle size, 292 sec disintegration time and 90.46% drug content. CONCLUSION: Drug release of the optimized batch (2F7) and marketed formulation (LANZOL cap) was found to be 82.33% and 80.07%, respectively. An accelerated study indicated that optimized formulation was stable.

Investigation of the bioequivalence of two lansoprazole formulations in healthy Chinese volunteers after a single oral administration.

The objective of this study was to compare two lansoprazole products (the reference brand enteric-coated capsules and the test generic enteric-coated tablets), and the key pharmacokinetic (PK) parameters for both formulations and their metabolites were assessed. The study used an open-label, randomized two-period crossover design with an 8-day washout period between doses in 24 healthy subjects under fasting conditions. The concentration of lansoprazole and its two metabolites was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The in vitro release of lansoprazole from the test and reference formulations was within the acceptable limits. The relationship between concentration and peak area ratio was found to be linear within the range for lansoprazole and metabolites. The point estimates (ratios of geometric mean) of lansoprazole and two main metabolites were between 94.3% and 105.1% for AUC0-t, AUC0-∞, and Cmax. No statistically significant difference between the two formulations was found. The results of in vitro and in vivo suggested equivalent clinical efficacy of the two brands.

Preparation and evaluation of enteric coated tablets of hot-melt extruded lansoprazole.

The objective of this work was to use hot-melt extrusion (HME) technology to improve the physiochemical properties of lansoprazole (LNS) to prepare stable enteric coated LNS tablets. For the extrusion process, we chose Kollidon® 12 PF (K12) polymeric matrix. Lutrol® F 68 was selected as the plasticizer and magnesium oxide (MgO) as the alkalizer. With or without the alkalizer, LNS at 10% drug load was extruded with K12 and F68. LNS changed to the amorphous phase and showed better release compared to that of the pure crystalline drug. Inclusion of MgO improved LNS extrudability and release and resulted in over 80% drug release in the buffer stage. Hot-melt extruded LNS was physically and chemically stable after 12 months of storage. Both formulations were studied for compatibility with Eudragit® L100-55. The optimized formulation was compressed into a tablet followed by coating process utilizing a pan coater using L100-55 as an enteric coating polymer. In a two-step dissolution study, the release profile of the enteric coated LNS tablets in the acidic stage was less than 10% of the LNS, while that in the buffer stage was more than 80%. Drug content analysis revealed the LNS content to be 97%, indicating the chemical stability of the enteric coated tablet after storage for six months. HME, which has not been previously used for LNS, is a valuable technique to reduce processing time in the manufacture of enteric coated formulations of an acid-sensitive active pharmaceutical ingredient as compared to the existing methods.

Lansoprazole and carbonic anhydrase IX inhibitors sinergize against human melanoma cells.

CONTEXT: Proton Pump Inhibitors (PPIs) reduce tumor acidity and therefore resistance of tumors to drugs. Carbonic Anhydrase IX (CA IX) inhibitors have proven to be effective against tumors, while tumor acidity might impair their full effectiveness. OBJECTIVE: To analyze the effect of PPI/CA IX inhibitors combined treatment against human melanoma cells. METHODS: The combination of Lansoprazole (LAN) and CA IX inhibitors (FC9-399A and S4) has been investigated in terms of cell proliferation inhibition and cell death in human melanoma cells. RESULTS: The combination of these inhibitors was more effective than the single treatments in both inhibiting cell proliferation and in inducing cell death in human melanoma cells. DISCUSSION: These results represent the first successful attempt in combining two different proton exchanger inhibitors. CONCLUSION: This is the first evidence on the effectiveness of a new approach against tumors based on the combination of PPI and CA IX inhibitors, thus providing an alternative strategy against tumors.

Application of (19) F time-domain NMR to measure content in fluorine-containing drug products.

It is necessary to show that the active content in the dosage form of drugs is within a certain narrow range of the label claim. In case of fluorinated drugs, the active content can be measured by high field solid state NMR because the excipients lack fluorine. To make NMR reachable to any laboratory, simple to use, and at a low cost, measurement of (19) F nucleus using a 23 MHz (for (1) H) low field benchtop time-domain (TD) NMR was investigated. Three fluorinated drug products, cinacalcet, lansoprazole, and ciprofloxacin, were chosen for this study. The doses for these drug products range from 15 to 500 mg. The average drug content measured using (19) F TD-NMR compares well with the reported label claims for the three drugs tested. (19) F TD-NMR is a simple and non-destructive technique to measure drug content in tablets. In addition, the accessibility and simplicity of the technique makes it an excellent process analytical technology tool for development and manufacturing in the pharmaceutical industry. Copyright © 2015 John Wiley & Sons, Ltd.

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.

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.