High-throughput LC-MS/MS Method for Simultaneous Determination of Pantoprazole and Atorvastatin in Rat Plasma: Application to a Pharmacokinetic Interaction Study.

BACKGROUND: Pantoprazole and atorvastatin are often used jointly in the clinic. The drug-drug interaction of pantoprazole and atorvastatin is worthy of being investigated. OBJECTIVE: A highly rapid, sensitive, and selective LC-MS/MS method was developed for simultaneous quantification of pantoprazole and atorvastatin in rat plasma. METHODS: Omeprazole and atorvastatin-d5 were used as the internal standards (ISs) of pantoprazole and atorvastatin, respectively. Simple protein precipitation was used to extract analytes from 50.0 µL plasma samples. RESULTS: The chromatographic separation was achieved on a C18 column and the total chromatographic run time was 3.2 min. Acquisition of mass spectrometric data was performed on a triple-quadrupole mass spectrometer in multiple- reaction-monitoring (MRM) mode with an ESI source using the transition m/z 384→ 200 for pantoprazole and m/z 559.4→ 440.2 for atorvastatin, respectively. The method was validated over the concentration range of 20.0 ∼ 5000 ng/mL for pantoprazole and 1.00 ∼ 250 ng/mL for atorvastatin. All the validation results, including linearity, specificity, precision, accuracy, extraction recovery, matrix effect, and stability, met the acceptance criteria as per FDA guidelines. CONCLUSION: This method was successfully applied to a pharmacokinetic interaction study in Wistar rats. The results revealed significant evidence for the drug-drug interaction between pantoprazole and atorvastatin.

A Sensitive, Simple and Direct Determination of Pantoprazole Based on a "Turn off-on" Fluorescence Nanosensor by Using Terbium-1,10-phenanthroline-silver Nanoparticles.

A new sensitive, simple, rapid, reliable and selective fluorometric method for the determination of pantoprazole (PAN) in human plasma and a pharmaceutical formulation has been developed. This technique is based on a quenching effect of silver nanoparticles (AgNPs) on the emission intensity of a fluorescent probe, terbium(III)-1,10-phenantroline (Tb(III)-phen) complex (due to a fluorescence resonance energy transfer (FRET) phenomenon between the Tb(III)-phen complex and AgNPs), and then restoring the fluorescence intensity of the Tb(III)-phen-AgNPs system upon the addition of PAN (turn off-on process). The effects of various factors on the proposed method including time, temperature, pH, order of the addition of various reagents and the concentration of AgNPs were investigated. Under the optimal conditions, a good linear relationship between the enhanced emission intensity of the Tb(III)-phen-AgNPs system and the PAN concentration was observed in the range of (10 - 1000) × 10-8 M. The limit of detection (LOD) and the limit of quantitation (LOQ) were 7.2 × 10-8 and 24.2 × 10-8 M, respectively. Also, the interferences of some common interfering species on the fluorescence intensity of the system were investigated. This simple and sensitive method was successfully applied for the determination of PAN in spiked human plasma samples and in its capsule formulation. The analytical recoveries were in the range of 88.54 - 101.33 and 90.07 - 98.85%, respectively.

Effect of food on the pharmacokinetics of omeprazole, pantoprazole and rabeprazole.

BACKGROUND: The pharmacokinetics of proton pump inhibitors (PPIs) may be affected by food intake. We aimed to evaluate the effect of food on the pharmacokinetics of omeprazole, rabeprazole, and pantoprazole. SETTING: The study population comprised 186 healthy volunteers participating in 6 bioequivalence clinical trials. METHOD: Subjects were evaluated to determine the effect of a high-fat breakfast on the pharmacokinetics of omeprazole (n = 36), rabeprazole (n = 69), and pantoprazole (n = 81). MAIN OUTCOME MEASURE: Drug plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. RESULTS: Food affected the pharmacokinetics of omeprazole (increased Tmax and decreased AUC and Cmax), pantoprazole (increased Tmax and decreased AUC), and rabeprazole (increased Tmax, Cmax and half-life). Food increased variability in Tmax for all 3 drugs, delaying absorption around 3 to 4 h and until 20 h in some subjects. CONCLUSION: As food delays the absorption of PPIs and increases their variability, it would be better to administer these drugs under fasting conditions. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database: EudraCT : 2004-003863-59 (registration date 05/MAR/2004), EudraCT 2006-001162-17 (registration date 17-MAR-2006), EudraCT: 2007-002489-37 (registration date 12-JUN-2007), EudraCT: 2007-002490-31 (registration date 12-JUN-2007), EudraCT: 2010-024029-19 (registration date 23-NOV-2010).

Simultaneous enantioselective determination of omeprazole, rabeprazole, lansoprazole, and pantoprazole enantiomers in human plasma by chiral liquid chromatography-tandem mass spectrometry.

Proton pump inhibitors, including omeprazole, rabeprazole, lansoprazole, and pantoprazole, achieved simultaneous enantioselective determination in the human plasma by chiral liquid chromatography-tandem mass spectrometry. The four corresponding stable isotope-labeled proton pump inhibitors were adopted as the internal standards. Each enantiomer and the internal standards were extracted with acetonitrile containing 0.1% ammonia, then separated with a Chiralpak IC column (5 µm, 4.6 mm × 150 mm) within 10 min. The mobile phase was composed of acetonitrile-ammonium acetate (10 mM) containing 0.2% acetic acid (50:50, v/v). To quantify all enantiomers, an API 4000 tandem mass spectrometer was used, and multiple reaction monitoring transitions were performed on m/z 360.1→242.1, 384.1→200.1, 370.1→252.1, and 346.1→198.1, respectively. No significant matrix effect was observed for all analytes. The calibration curve for all enantiomers were linear from 1.25 to 2500 ng/mL. The precisions for intra- and inter-run were < 14.2%, and the accuracy fell in the interval of -5.3 to 8.1%. Stability of samples was confirmed under the storage and processing conditions. The developed method was also suitable for separation and determination of ilaprazole enantiomers. The validated method combining the equilibrium dialysis method was applied to the protein binding ratio studies of four pairs proton pump inhibitor enantiomers in human plasma.

Esomeprazole vs pantoprazole effects on cyclosporine levels in kidney transplantation: A randomized clinical trial.

Renal allograft survival requires multiple immunosuppressive drugs. This strategy may lead to gastric complications that necessitate gastro-protective medications, notably, proton pump inhibitors (PPI). This study aimed to compare the influence of pantoprazole and esomeprazole on serum cyclosporine trough levels (C0 ) in renal transplant recipients (RTR). A prospective, parallel, open-label trial was conducted on 47 adult RTR receiving cyclosporine doses adjusted to attain trough concentrations of 100 to 150 µg/L, mycophenolate mofetil (MMF) 750 mg q12 hour and prednisolone at 5 mg daily at Nasser Institute, Cairo, Egypt from January to September 2016. Patients were randomized into the esomeprazole group (25) or pantoprazole group (22) receiving the same dose (40 mg once daily). The study outcomes included clinical signs of rejection and renal function decline, assessed by elevations in serum creatinine, caused by cyclosporine level variations in either of the two study groups. Renal function, C0 and CBC measurements were measured at baseline and monthly for 6 months. The mean C0 values were higher in the pantoprazole group than in the esomeprazole group in the sixth month only (P = .007). Serum creatinine level was lower in the sixth month than at baseline in the esomeprazole group (P = .004). There were no signs of rejection biochemical or clinical in any of the study groups. In conclusion, PPIs should be used with caution and doses should be titrated to reach the C0 targets in RTR, which is of more importance in pantoprazole than esomeprazole to avoid C0 level elevation or decline affecting the allograft function.

A new strategy for extraction and depuration of pantoprazole in rat plasma: Vortex assisted dispersive micro-solid-phase extraction employing metal organic framework MIL-101(Cr) as sorbent followed by dispersive liquid-liquid microextraction based on solidification of a floating organic droplet.

Dispersive micro-solid-phase extraction (DMSPE) combined with dispersive liquid-liquid microextraction based on the solidification of a floating organic droplet (DLLME-SFO) was successfully developed for extraction and depuration of pantoprazole in rat plasma. The remarkable metal organic framework (MOF), MIL-101(Cr) was used as DMSPE adsorbent. The detection of pantoprazole was performed by convenient HPLC-UV. In the extraction of pantoprazole from plasma samples, small molecule compounds, including the target and abundant impurities, were easily admitted into the porous structure of MIL-101 (Cr) material in DMSPE; while, macromolecular compounds were handily excluded from the adsorbent. Next, the depuration process was achieved by removal of small polar impurities in DLLME-SFO. Influential factors were systematically optimized for ideal enrichment and depuration efficiency. Under the optimal conditions, a satisfactory linearity range from the lower limit of quantification (LLOQ, 100 ng/L) to 10 000 ng/L with the correlation coefficients (r) of 0.9934 was obtained. The LLOQ was 100 ng/mL and the relative recoveries were ≧ 73.2 ±â€¯4.8%. The approving reproducibility, acceptable accuracy, and stability were all within the acceptance limits. This proposed method presented the advantages of environment-friendly, low-cost, recyclable, low impurity, and preferable applicability. It could offer a new idea for the pretreatment and pharmacokinetic study of pantoprazole in rat plasma.

Clopidogrel in Critically Ill Patients.

Only limited data are available regarding the treatment of critically ill patients with clopidogrel. This trial investigated the effects and the drug concentrations of the cytochrome P450 (CYP450) activated prodrug clopidogrel (n = 43) and the half-life of the similarly metabolized pantoprazole (n = 16) in critically ill patients. ADP-induced aggregometry in whole blood classified 74% (95% confidence intervals 59-87%) of critically ill patients as poor responders (n = 43), and 65% (49-79%) responded poorly according to the vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. Although the plasma levels of clopidogrel active metabolite normally exceed the inactive prodrug ∼30-fold, the parent drug levels even exceeded those of the metabolite 2-fold in critically ill patients. The half-life of pantoprazole was several-fold longer in these patients compared with reference populations. The inverse ratio of prodrug/active metabolite indicates insufficient metabolization of clopidogrel, which is independently confirmed by the ∼5-fold increase in half-life of pantoprazole. Thus, high-risk patients may benefit from treatment with alternative platelet inhibitors.