The management of hyperphosphatemia is of critical significance given its high prevalence among hemodialysis (HD) patients and its strong association with worse outcomes. Clinical pharmacists can play a crucial role in medication management, but there is a critical shortage. Currently, there is rarely study evaluating how pharmacists in different roles can engage in medication management. The main aim of this study was to evaluate the impact of a pharmacist-led intervention using a hierarchical management model on hyperphosphatemia. A parallel, prospective, randomized, multicenter study was designed including patients at 9 recruited Dialysis Centers whose serum phosphate (sP) > 4.5 mg/dL with maintenance HD. Every Dialysis Center was allocated one pharmcist, primary management pharmacists (PMP) or senior management pharmacists (SMP), who was responsible for education. After 6-month study, the sP in the intervention group decreased from 6.36 ± 1.30 mg/dL to 5.55 ± 1.34 mg/dL, and was much lower than control group (6.02 ± 1.53 mg/dL) (p < 0.05). But the nutritional indicators, such as albumin and hemoglobin hadn’t been affected (p > 0.05). Importantly, both PMPs and SMPs achieved clinically meaningful reductions in sP (p < 0.05 for both within-group comparisons), with no statistically significant difference between the two groups (p = 0.11). These findings suggest that a hierarchical pharmacist management model—combining standardized education with targeted SMP support for high-risk patients—can enable PMPs to deliver care comparable to that of SMPs. This approach may help optimize limited pharmacy resources and expand access to high-quality medication management for hemodialysis patients with hyperphosphatemia.

Toxic epidermal necrolysis (TEN) is a rare and low incidence rate disease characterized by pirfenidone-induced skin damage. Pirfenidone is a new anti-fibrotic and anti-inflammatory drug that can alleviate the deterioration of lung function in patients with COVID-19-induced pneumonia and prolong the progression-free survival period. However, side effects of pirfenidone have drawn widespread attention, which include gastrointestinal symptoms, liver damage, skin photosensitivity, and rash. So far, many cases caused by pirfenidone have been reported. As far as we know, cases of TEN induced by pirfenidone have rarely been reported. This article presents cases of TEN induced by pirfenidone, so that clinicians can be aware of the possibility of TEN when using pirfenidone, and how to use inflammation-relevant indicators for evaluating the severity and risk of death of TEN, which has potential clinical value.

Background: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). The clinical efficacy and safety of an administered tofacitinib, either monotherapy or in combination with conventional synthetic disease-modifying anti-rheumatic drugs, mainly methotrexate (MTX), have been evaluated. The high plasma concentration with delayed medicine clearance may affect the liver and/or kidney functions. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC- MS/MS) method for the quantitative analysis of methotrexate, tofacitinib, and metabolite M9 in plasma of Sprague Dawley (SD) rats was developed, and its effectiveness was validated as well. Methods: Methotrexate, tofacitinib, M9 and fedratinib (internal standard, IS) were separated by gradient elution. The chromatography was performed on an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 μm) column with the mobile phases of acetonitrile and 0.1% formic acid aqueous solution with different proportions at the flow rate of 0.30 mL/min. In the positive ionization mode, the analyzes were detected using a Xevo TQ-S triple quadrupole tandem mass spectrometer, with the following mass transition pairs: m/z 313.12 → 148.97 for tofacitinib, m/z 329.10 → 165.00 for M9 and m/z 455.12 → 308.05 for methotrexate. Results: The obtained results manifested good calibration linearity over the ranges of tofacitinib at 0.1-100 ng/mL, M9 at 0.05-100 ng/mL, and methotrexate at 0.05-100 ng/mL. The lower limit of quantifications (LLOQs) of methotrexate, tofacitinib and M9 were 0.05 ng/mL, 0.1 ng/mL and 0.05 ng/mL, respectively. Intra-day and inter-day accuracy values were confirmed with a range of -6.3% to 12.7%, while intra-day and inter-- day precision values were ≤14.4%. Additionally, recoveries were greater than 86.5% for each compound without significant matrix effects. Conclusion: The currently established analytical method exhibited great potential for the evaluation of plasma concentrations of methotrexate, tofacitinib and M9 simultaneously, greatly reducing the detection time, which would serve as a supplementary role in formulating dose decisions to achieve personalized treatment, identify drugs that cause adverse reactions and finally, to assess drug-drug interactions on clinical studies.

Abstract Man, 55-year-old, developed Sagliker syndrome (SS) in the course of hemodialysis for end-stage renal disease from 2008, as a result of uncontrolled secondary hyperparathyroidism (SHPT). His medical managements failed and he had no chance of kidney transplantation. Although surgical parathyroidectomy was rejected and the disease development could not be reversed, PTH began to decline and SS progressed slowly under the control of management and guidance in medication treatment. It is possible that such patients can survive with long-time dialysis, but the prevention of severe SHPT is critical.

The main objective of our current study is to develop and validate an accurate and direct ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to simultaneously detect plasma concentrations of tofacitinib and its metabolite M9, and to study the pharmacokinetic profiles of the two compounds in beagle dogs. After rapid precipitation of protein by adding acetonitrile, the chromatographic separation of tofacitinib was completed, as well as M9 and upadacitinib (internal standard, IS) by using an Acquity BEH C18 (1.7 μm, 2.1 mm × 50 mm) column. A Xevo TQ-S triple quadrupole tandem mass spectrometer was employed to determine their concentrations under the positive ion pattern. Selective reaction monitoring (SRM) was used with ion transitions at m/z 313.12 → 148.97 for tofacitinib, m/z 329.10 → 137.03 for M9, and m/z 380.95 → 255.97 for IS, respectively. This assay demonstrated excellent linearity, and the ranges of calibration curves for both tofacitinib and M9 were 0.5–400 ng/mL. The new UPLC-MS/MS assay can reach the values (0.5 ng/mL) of lower limit of quantification (LLOQ) for both tofacitinib and M9. Both intra-day and inter-day accuracy of all analytes ranged from −12.0% to 14.3%, while the precision was ≤13.2%. The recovery rate of all analytes was >88.5%, and more importantly there was no conspicuous matrix effect. In addition, the stability was consistent with the quantificative requirements of plasma samples under all conditions. Finally, the assay on UPLC-MS/MS is able to be employed to determine the pharmacokinetic characteristics of tofacitinib and its metabolite M9 in the plasma of beagle dogs after taking orally a dose of tofacitinib at 2 mg/kg.

目的 了解中国临床药师工作的开展情况,为促进临床药学学科规范化发展提供参考.方法 通过文献查阅我国临床药师的配备、设施、工作成效等情况.结果 我国基本建立临床药师制,合理用药软件配备率较高,临床药师在合理用药方面取得一定成效,得到临床认可,但我国临床药师制起步较晚,基层医院门槛偏低,多数医院人员配备不足,实验室工作开展不多,发展不均衡.结论 为进一步提升我国临床药师工作,提出几点建议:完善我国临床药学教育培养体系;开展临床药师专项继续教育工作;建议将临床药师纳入行政编列;优化数据填报工作,开发统一信息系统.

As multi-targeted tyrosine kinase inhibitors, sorafenib, regorafenib and cabozantinib are widely used in hepatocellular carcinoma (HCC) for systemic therapies with anti-proliferative and anti-angiogenic effects. Nevertheless, adverse effects or insufficient efficacy appear frequently due to the plasma concentration with individual variability of these drugs. To ensure the curative effect and safety by therapeutic drug monitoring (TDM), this study developed a high throughput method to quantify sorafenib, regorafenib, cabozantinib and their active metabolites in plasma simultaneously. The chromatographic separation analysis achievement was performed on a Waters-ACQUITY UPLC BEH C18 column by UPLC-MS/MS system using a gradient elution of solvent A (acetonitrile) and solvent B (water with 0.1% formic acid) in 3.0 min. This method presented satisfactory results of specificity, precision (the intra-day coefficient of variation was between 2.5% and 6.6%, and the inter-day coefficient of variation was between 4.0% and 11.1%) and accuracy (within ±15% for intra-day and inter-day), as well as the stability under certain conditions, the matrix effect in plasma, and extraction recovery (75.6%–94.4%). The linearity of each analyte in the proper concentration scope indicated excellent. This study strictly complied with the performance rules of assay validation in biological medium proposed by FDA and was successfully applied to the pharmacokinetic study in rats. Thus, it would be an advantageous option to research the relationship between concentration-efficacy and concentration-toxic in HCC patients who were supposed to take these medications.

A 58-year-old male patient received quadruple therapy with amoxicillin 1 g, furazolidone 0.1 g, rabeprazole 20 mg, and bismuth potassium citrate 0.6 g twice daily for Helicobacter pylori infection for 4 weeks. Seven days after drug withdrawal, the laboratory tests showed serum creatinine (Scr) 469 μmol/L and blood urea nitrogen (BUN) 19.2 mmol/L. Renal biopsy showed acute tubular injury. The Scr level was 78 μmol/L in the physical examination of 6 months ago. Acute kidney injury was considered to be associated with the quadruple therapy. Methylprednisolone, rebamipide, and calcium carbonate were given orally. Four weeks later, the laboratory tests showed Scr 171 μmol/L and BUN 14.4 mmol/L and the above treatments were continued; 12 weeks later, his Scr was 140 μmol/L and BUN was 11.4 mmol/L.

Abstract Context As an inhibitor cytochrome P450 family 2 subfamily C polypeptide 8 (CYP2C8), quercetin is a naturally occurring flavonoid with its glycosides consumed at least 100 mg per day in food. However, it is still unknown whether quercetin and selexipag interact. Objective The study investigated the effect of quercetin on the pharmacokinetics of selexipag and ACT-333679 in beagles. Materials and methods The ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate the pharmacokinetics of orally administered selexipag (2 mg/kg) with and without quercetin (2 mg/kg/day for 7 days) pre-treatment in beagles. The effect of quercetin on the pharmacokinetics of selexipag and its potential mechanism was studied through the pharmacokinetic parameters. Results The assay method was validated for selexipag and ACT-333679, and the lower limit of quantification for both was 1 ng/mL. The recovery and the matrix effect of selexipag were 84.5–91.58% and 94.98–99.67%, while for ACT-333679 were 81.21–93.90% and 93.17–99.23%. The UPLC-MS/MS method was sensitive, accurate and precise, and had been applied to the herb-drug interaction study of quercetin with selexipag and ACT-333679. Treatment with quercetin led to an increased in C max and AUC0–t of selexipag by about 43.08% and 26.92%, respectively. While the ACT-333679 was about 11.11% and 18.87%, respectively. Discussion and conclusion The study indicated that quercetin could inhibit the metabolism of selexipag and ACT-333679 when co-administration. Therefore, the clinical dose of selexipag should be used with caution when co-administered with foods high in quercetin.

The contribution of the metabolites of linezolid to the associated myelosuppression is unknown in patients who are renal impairment. In this research, the purpose of our experiment was to explore and develop a quick and robust ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay for the determination of linezolid and its metabolite PNU-142300 in human serum simultaneously. The analytes were prepared using a simple and convenient approach with acetonitrile for protein crash, and then separated from the matrix on a Waters Acquity Ultra performance liquid chromatography (UPLC) BEH C18 (2.1 mm × 50 mm, 1.7 μm) column in a program of gradient elution, where the mobile phase was consisted of water with 0.1% formic acid and acetonitrile, and was placed at 0.40 ml/min flow rate. Multiple reaction monitoring (MRM) was employed and conducted for UPLC-MS/MS detection with ion transitions at m/z 338.01 → 296.03 for linezolid, m/z 369.96 → 327.98 for PNU-142300 and m/z 370.98 → 342.99 for tedizolid (Internal standard, IS), respectively. This method had good linearity respectively in the calibration range of 0.01–20 μg/ml for linezolid, and 0.05–100 μg/ml for PNU-142300. In the intra- and inter-day, the precision of linezolid and PNU-142300 was below 14.2%, and the accuracy in this method was determined to be from −9.7 to 12.8%. In addition, recovery and matrix effect of the analytes were all found to be acceptable, and the analytes during the assay and storage in serum samples were observed to be stable. The novel optimized UPLC-MS/MS assay was also successfully employed to determine the concentration levels of linezolid and PNU-142300 in human serum. The results showed that linezolid-associated myelosuppression occurs more frequently in patients with renal insufficiency, and the metabolite-to-parent concentration ratio of PNU-142300 is predicted to reduce this toxicity of myelosuppression.

Elagolix, as a competitive gonadotropin-releasing hormone (GnRH) receptor antagonist, has been recently approved by the US FDA for the management of moderate to severe pain due to endometriosis in women. In this study, we developed and verified an analysis assay to detect the concentration level of elagolix in plasma from rats after sample preparation based on a newly validated ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technique in this study. The process of sample preparation used acetonitrile for a quick and easy protein precipitation method and diazepam was engaged as the internal standard (IS). Then, gradient elution was used to elute elagolix and IS. The mobile phase used in the present experiment was consisted of solvent A (acetonitrile) and solvent B (water having formic acid with the volume ratio of 0.1%), and the type of the C18 column used was named Acquity UPLC BEH C18 column with the specification of 2.1 mm × 100 mm, 1.7 μm. Multiple reaction monitoring (MRM) in positive ion mode for the experiment was engaged to detect the level of elagolix with electrospray ionization (ESI) source by m/z 632.4 → 529.5 transition for quantification and m/z 632.4 → 177.1 transition for qualification. It was found that the method in the scope of 1–2000 ng/mL indicated excellent linearity (r2 > 0.9983). The precision of this assay for intra-day was between 3.5 and 5.5%, and for inter-day was between 9.4 and 12.7%, respectively; the accuracy was 1.2–13.9% for the intra- and inter-day. The stability, extraction recovery, and matrix effect of the method were all in accordance with the rules of assay validation in biological medium proposed by FDA, whose application was also successfully used to determine the concentration of plasma elagolix from an experiment on pharmacokinetic investigation after oral administration of 15 mg/kg elagolix.

Vortioxetine is currently used as the first-line therapy drug for major depressive disorder (MDD). In the present study, we aimed to develop and fully validate an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous quantification of vortioxetine and its major metabolite Lu AA34443 in plasma and to investigate the effects of dronedarone and amiodarone on vortioxetine metabolism in rats. After protein precipitation with acetonitrile, the separation of vortioxetine, Lu AA34443 and duloxetine (internal standard, IS) were finished on an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 μm) column and their detections were conducted by a Xevo TQ-S triple quadrupole tandem mass spectrometer in the positive ion mode. The assay displayed excellent linearity in the range of 0.5–50 ng/mL for vortioxetine, and 5–1000 ng/mL for Lu AA34443. The results of this method exhibited that the precision, accuracy, matrix effect, recovery, and stability of vortioxetine and Lu AA34443 met all requirements for the quantitation in plasma samples. The validated assay was further successfully employed to study the effects of dronedarone (80 mg/kg) and amiodarone (60 mg/kg) on vortioxetine metabolism in rats. The results showed that dronedarone and amiodarone could increase the concentration of vortioxetine and have inhibitory effect on vortioxetine metabolism. Thus, vortioxetine dose interruption or reduction may be considered.

BACKGROUND:CYP/CYP450 2C19 (CYP2C19) is a highly polymorphic enzyme and exhibits individual differences in metabolic activity. The purpose of this research was mainly to explore the catalytic activities of 30 CYP2C19 variants on the substrate voriconazole in vitro, including 24 novel CYP2C19 variants (2C19.2E-.2H, .2J, .3C, .29-.33, L16F, 35FS, R124Q, R125G, T130M, N231T, M255T, R261W, N277K, S303N, I327T, N403I, and A430V) found in Chinese Han population for the first time.METHODS:These CYP2C19 variants were expressed in Spodoptera frugiperda (Sf) 21 insect cells using the baculovirus-mediated expression system. The substrate voriconazole was incubated with the abovementioned proteins at 37°C for 30 minutes in an appropriate designed system. Then through detecting its major metabolite voriconazole N-oxide by ultra-performance liquid chromatography tandem mass spectrometry, available data were obtained to explain the influence of CYP2C19 polymorphisms on voriconazole.RESULTS:From the results, when compared to CYP2C19.1, most variants exhibited either reduced Vmax and/or increased Km value, indicating that the intrinsic clearance (Vmax/Km ) values of most variants were significantly altered. The catalytic activities of 20 novel variants exhibited decreases in different degrees compared to CYP2C19.1, with relative clearance values ranging from 1.11% to 83.78%. However, L16F exhibited the increased catalytic activity for 135.68%. In addition, the kinetic parameters of four variants (2C19.2H, .3, 35FS, and R124Q) could not be detected, due to the defective gene.CONCLUSION:This is the first study to report the effects of CYP2C19 polymorphisms on vori-conazole metabolism in vitro, and we hope these data could lay the foundation for the early clinical research and individualized treatment.

Background CYP2D6 is one of the most important members of the cytochrome P450 superfamily. Its genetic polymorphism significantly influences the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. Methods and results The aim of this research was mainly to explore the catalytic activities of 22 newly reported CYP2D6 isoforms (2D6*87, *88, *89, *90, *91, *92, *93, *94, *95, *96,*97, *98, *R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C, R497C) on dapoxetine in vitro. The research was designed with an appropriate incubation system in test tubes and carried out in the constant temperature water. Through detecting its two metabolites desmethyldapoxetine and dapoxetine-N-oxide, the available data were obtained to explain the influence of CYP2D6 polymorphism on the substrate drug dapoxetine. As a result, the intrinsic clearance (Vmax/Km) values of most variants were significantly altered when compared with the counterpart of CYP2D6*1, with most of these variants exhibiting either reduced Vmax and/or increased Km values. For dapoxetine demethylation pathway (which produces desmethyldapoxetine), 2D6*89 and E215K exhibited no markedly decreased relative clearance of 92.81% and 97.70%, respectively. The relative clearance of rest 20 variants exhibited decrease in different levels, ranging from 20.44% to 90.90%. For the dapoxetine oxidation pathway (which produces dapoxetine-N-oxide), the relative clearance values of three variants, 2D6*90, *94, and V342M, exhibited no markedly increased relative clearance of 106.17%, 107.78%, and 109.98%, respectively; the rest 19 variants exhibited significantly decreased levels ranging from 27.56% to 84.64%. In addition, the kinetic parameters of two CYP2D6 variants (2D6*92 and 2D6*96) could not be detected, due to the defect of the CYP2D6 gene. Conclusion As the first report of all aforementioned alleles for dapoxetine metabolism, these data may help in the clinical assessment of the metabolic elimination of dapoxetine and may provide fundamental information for further clinical studies.

Hemangeol, approved for the treatment of proliferative infantile hemangiomas requiring systemic therapy, is metabolized by cytochrome P450 2D6 (CYP2D6), which is a highly polymorphic enzyme that metabolizes a large number of drugs. More than 100 CYP2D6 allelic variants have been reported so far, including 22 novel variants that discovered in our lab in the Chinese population. Our study aimed to probe the enzymatic activity of these variants toward hemangeol in vitro with recombinant microsomes that expressed in sf21 insect cells using a baculovirus-mediated expression system.

Cytochrome P450 enzyme 2D6 (CYP2D6) is an important member of the cytochrome P450 enzyme superfamily, with more than 100 CYP2D6 allelic variants being previously reported. The aim of this study was to assess the catalytic characteristics of 25 alleles (CYP2D6.1 and 24 CYP2D6 variants) and their effects on the metabolism of propafenone in vitro. Twenty-five CYP2D6 alleles were expressing in 21 Spodoptera frugiperda (Sf) insect cells, and each variant was evaluated using propafenone as the substrate. Reactions were performed at 37 degrees C with 1-100 mu mol/L propafenone for 30 min. After termination, the product 5-OH-propafenone was extracted and used for signal collection by ultra-performance liquid chromatography (UPLC). Compared with wild type CYP2D6.1, the intrinsic clearance (V-max and K-m) values of all variants were significantly altered. Three variants (CYP2D6.87, CYP2D6.90, CYP2D6.F219S) exhibited markedly increased intrinsic clearance values (129% to 165%), whereas 21 variants exhibited significantly decreased values (16% to 85%) due to increased K-m and (or) decreased V-max values. These results indicated that the majority of tested alleles had significantly altered catalytic activity towards propafenone hydroxylation in this expression system. Attention should be paid to subjects carrying these rare alleles when treated with propafenone.

Isavuconazole (ISA) is a new generation, broad-spectrum triazole with efficacy against invasive fungal diseases including aspergillosis and mucormycosis.

The objective of this study was to assess the catalytic activity of 22 novel CYP2D6 allelic variants (2D6*87-*98, R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C and R497C) to olanzapine in vitro. Their protein products expressed in Spodoptera frugiperda 21 (Sf21) insect cells were incubated with olanzapine 100-2,000 μmol/l for 30 min. The kinetic parameters of Km, Vmax and intrinsic clearance were determined by 2-hydroxymethylolanzapine, the metabolite of olanzapine mediated by CYP2D6, using ultra-performance liquid chromatography tandem mass spectrometry. Results showed that the kinetic parameters of 2 alleles, CYP2D6*92 and 2D6*96, could not be detected; 17 allelic variants, CYP2D6*87-*88, 2D6*90-*91, 2D6*93-*95, 2D6*97, R25Q, F164L, E215K, F219S, V327M, V342M, R344Q, R440C and R497C, significantly reduced the intrinsic clearance of olanzapine; 2 variants, CYP2D6*89 and 2D6*98, increased the intrinsic clearance of olanzapine; no difference was found in intrinsic clearance of D336N. Furthermore, 6 alleles, CYP2D6*87, 2D6*88, 2D6*91, 2D6*93, 2D6*97 and R497C, exhibited higher Km values in a range of 120.80-217.56% relative to wild-type CYP2D6*1. The research demonstrated the metabolic phenotype of the 22 novel CYP2D6 variants for olanzapine that were different from probe drugs we used previously and might provide beneficial information to the personalized medicine of olanzapine.

The aim of this study was to establish a rapid and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of concentration of sunitinib and its active metabolite N-desethyl sunitinib in rat plasma. The sunitinib and its active metabolite and the internal standard (apartinib) were separated on an Acquity UPLC BEH C18 chromatography column (2.1 x 50 mm, 1.7 mu m) using gradient elution with a mobile phase of acetonitrile and 1% formic acid in water at a flow rate of 0.4 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode to monitor the precursor-to-product ion transitions of m/z 399.1 -> 283.1 for sunitinib, m/z 371.2 -> 283.2 for N-desethyl sunitinib and m/z 398.3 -> 212.1 for apartinib (IS) using a positive electrospray ionization interface. The method was validated for 0.1-1000 ng/mL for both sunitinib and N-desethyl sunitinib using 100 mu L of plasma sample. Total time for each chromatograph was 2.5 min. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels exhibited relative standard deviations (RSD) < 10.5% and the accuracy values ranged from -11.5% to 10.2%. The method was successfully applied to a pharmacokinetic study of sunitinib in rats after oral administration.