Objectives: AC02, a novel synthetic peptide derived from ACTH, is being developed as a potential therapeutic alternative to porcine ACTH1-39 for use in infantile spasms. Methods: The study comprised single-ascending dose cohorts (0.02, 0.04, 0.08, 0.16 mg/kg AC02) and multiple-ascending dose cohorts (0.04, 0.08 mg/kg AC02 daily for 5 days). A separate positive-control arm received porcine ACTH1-39 (25 U/day for 5 days). PD effects (free and total cortisol) were compared head-to-head with the positive control. Plasma concentrations of AC02, porcine ACTH1-39, free and total cortisol were quantified by validated LC-MS/MS methods, and anti-drug antibody responses were measured using a validated electrochemiluminescence bridging immunoassay. Population PK/PD modeling characterized the concentration–response relationships for free cortisol. Results: Across the 0.02–0.16 mg/kg dose range, AC02 exhibited approximately dose-proportional pharmacokinetics and no accumulation after multiple doses. At 0.04 and 0.08 mg/kg, the baseline-corrected effects on free cortisol were generally consistent with those of porcine ACTH1-39. Dynamic monitoring of the free cortisol fraction revealed a biphasic pattern across all groups: an early peak followed by a later rise. Total cortisol, by contrast, showed only a monophasic decline, indicating the limitations of total cortisol as a sole PD biomarker. No unexpected safety signals were observed. At 0.04 mg/kg, AC02 demonstrated pharmacodynamic responses comparable to those of marketed ACTH product based on the biologically active component of free cortisol, with favorable safety and pharmacokinetic profiles. Conclusions: This first-in-human study demonstrates that AC02 has favorable pharmacokinetic properties, and an acceptable safety profile.

Lumateperone is an antipsychotic metabolised to four active metabolites IC200131, IC200161, IC200565 and IC201308, which are closely related to its clinical efficacy and safety.For evaluating the clinical pharmacokinetics of lumateperone and its active metabolites in Chinese subjects, a high-throughput LC-MS/MS method was developed and validated for the simultaneous quantification of lumateperone and its four metabolites in human plasma. Chromatographic separation was achieved using an alkaline mobile phase and a bidentate silane column (Zorbax Extend-C18) with two-step gradient elution, which overcame peak tailing and carryover while enabling rapid analysis. The calibration ranges were 0.100-80.0 ng/mL for lumateperone and IC200131, 0.0400-32.0 ng/mL for IC200161 and IC201308, and 0.150-30.0 ng/mL for IC200565.The validated method was successfully applied to a pharmacokinetic study of lumateperone tosylate capsules. The clinical trial was registered at the Chinese Clinical Trial Registry (identifier: CTR20242699). Under fasting conditions, the mean Cmax values were 30.6 ng/mL for lumateperone, with corresponding AUC0-t values of 72.8 h·ng/mL. Under fed conditions, food delayed absorption and decreased Cmax for all analytes.This study reports the first comprehensive pharmacokinetic profiles of lumateperone and its four active metabolites in Chinese subjects. The validated method provides a robust foundation for pharmacokinetic research of lumateperone in humans.

Recently, the approval of Trop-2 targeted antibody drug conjugate (ADC) has changed the dilemma of patients with advanced triple-negative breast cancer who rely on chemotherapeutics to improve their survival. FDA018, an ADC consisting of an anti-Trop-2 antibody conjugated with a topoisomerase inhibitor SN-38 via an acid-cleavable linker, is currently being investigated in clinical trials. Based on the urgent demand to evaluate the clinical pharmacokinetics of FDA018, ligand binding assays (LBAs) for the determination of SN-38-conjugated antibody and total antibody and LC-MS/MS methods for the determination of the free SN-38, its metabolite SN-38G and total SN-38 were developed. The comparability and DAR sensitivity evaluation of the ELISA strategies for SN-38-conjugated antibody and total antibody were emphasized. The sensitivity of the LC-MS/MS method for the simultaneous determination of SN-38 and SN-38G reached 0.500 ng/mL and 0.250 ng/mL, respectively. An effective solution has been proposed for the optical instability of the cleavable linker of FDA018 during the pretreatment process of biological samples. The established bioanalytical methods were comprehensively validated and the results satisfied the acceptable criteria of ICH M10. The validated bioanalytical methods have been applied to the single-dose pharmacokinetic study of FDA018 in patients with Trop-2-positive malignant tumors successfully, and the pharmacokinetic profiles of FDA018 and its constituent components were investigated.

Purpose To evaluate the drug-drug interactions (DDI) of tunodafil (youkenafil), a novel phosphodiesterase type 5 inhibitor, its inhibitory effects on CYP450 enzymes in vitro and its clinical trials in combination with ritonavir or omeprazole were conducted. Methods The inhibitory effect of tunodafil on seven major CYP450 enzymes in human liver microsomes was investigated by probe substrate method. The effect of tunodafil on the pharmacokinetics of omeprazole (CYP2C19 substrate) in 40 healthy subjects, who received a single dose of 40 mg omeprazole in combination with tunodafil on the day 8 after taking 100 mg tunodafil daily for 7 days, was assessed based on CYP2C19 genotypes. The clinical DDI of ritonavir (potent CYP3A4 inhibitor) on tunodafil was studied in 28 healthy subjects who received a single dose of 50 mg tunodafil in combination with ritonavir on the day 6 after taking ritonavir twice a day for 5 days. Results Tunodafil showed moderate inhibition on CYP2C19 and CYP3A4/5 in vitro. When co-administration omeprazole with tunodafil, the AUC of omeprazole in the Extensive, Intermediate and Poor Metabolizers increased by 26%, 37% and 21%, respectively. After co-administration tunodafil with ritonavir, ritonavir increased the AUC and Cmax of tunodafil in human by about 78- fold and 13-fold respectively. Conclusions Tunodafil slightly increased omeprazole exposure in the Extensive and Intermediate Metabolizers of CYP2C19, but had no significant effect on omeprazole exposure in the Poor Metabolizers. Ritonavir could strongly inhibit the metabolism of tunodafil, and the combination of tunodafil with ritonavir should be prohibited.

FDA018, a novel trophoblast cell surface antigen 2-targeted antibody-drug conjugate, is designed for treating trophoblast cell surface antigen 2-positive solid tumors, including triple-negative breast cancer, lung cancer, and gastric cancer. In this study, a single-center, open-label, dose-escalation clinical study was conducted to evaluate the pharmacokinetics (PK) and immunogenicity of FDA018 injection in patients with advanced or metastatic epithelial malignant solid tumors, using an "accelerated titration" design and a standard "3+3" design across 6 dose cohorts (2.5, 5, 7.5, 10, 12 and 15 mg/kg). PK profiles were investigated for a topoisomerase I inhibitor (SN-38)-conjugated antibody, total antibody, unconjugated SN-38, a glucuronate metabolite of SN-38 (SN-38G), and total SN-38. To evaluate the impact of immunogenicity on PK profiles of FDA018, immunogenicity was assessed with an electrochemiluminescence-based bridging immunoassay. PK results showed that the exposure of the SN-38-conjugated antibody increased linearly with dose escalation. The terminal half-life of the SN-38-conjugated antibody (about 30 hours) was significantly shorter than that of the total antibody (about 85 hours). The terminal half-life of the SN-38-conjugated antibody and total antibody appeared to be prolonged after multiple administrations. The exposure of unconjugated SN-38 accounted for approximately 1% of total SN-38, indicating that most SN-38 remained conjugated to the monoclonal antibody in the systemic circulation, and the off-target toxicity was controllable. The accumulation analysis results showed that total antibody accumulated after multiple administrations. For immunogenicity assessment, among 20 patients receiving doses from 7.5 to 15 mg/kg, 15% tested positive for anti-drug antibodies. Anti-drug antibody-positive results did not significantly affect the PK profiles of FDA018. In conclusion, FDA018 demonstrated promising PK and immunogenicity profiles and laid a solid foundation for further clinical research. SIGNIFICANCE STATEMENT: This study comprehensively evaluated the clinical pharmacokinetic and immunogenicity of the trophoblast cell surface antigen 2-targeted antibody-drug conjugate, FDA018, for the first time, to the authors' knowledge. Compared with the commercially available trophoblast cell surface antigen 2-targeted antibody-drug conjugate sacituzumab govitecan, FDA018 showed promising pharmacokinetic properties with higher exposure of conjugated antibody and lower exposure of unconjugated SN-38 in vivo, implying better efficacy and lower off-target toxicity.

IntroductionKetamine is a significant class of antidepressant drugs, and the pharmacokinetic and pharmacodynamic characteristics of its enantiomers exhibit differences. Among them, intravenous infusion of (R)-ketamine can effectively alleviate depressive symptoms in patients, offering the advantages of prolonged duration of action and minimal side effects. The extensive preclinical pharmacokinetic (PK) studies of (R)-ketamine were conducted to support its further development.MethodsThis study investigated the preclinical pharmacokinetic behavior of (R)-ketamine across different dose groups through single- and multiple-dose pharmacokinetic studies in rats and dogs, along with tissue distribution studies in Sprague-Dawley (SD) rats.In vitro metabolism study using microsomes from mice, rats, dogs, monkeys, and humans were conducted to evaluate metabolic stability and obtain metabolite profiles. The excretion studies in rats (7.5 mg/kg dose group) were performed to elucidate the primary elimination pathways of (R)-ketamine. The allometric scaling approach was employed to predict human plasma total clearance based on preclinical data.Results(R)-ketamine exhibits nonlinear pharmacokinetics in SD rats and Beagle dogs, with plasma exposure increasing disproportionately to dose after both single and multiple intravenous administrations. The highest tissue exposure to (R)-Ketamine was found in the fat and kidney of the rats. The (R)-ketamine concentration ratio of brain/plasma was 2.25 for the rats, indicating effective blood-brain barrier penetration and significant brain distribution of (R)-ketamine. (R)-ketamine undergoes rapid metabolism in liver microsomes from mice, rats, dogs, monkeys and humans. The predominant metabolite identified in human, monkey and mice liver microsomes was (R)-norketamine and demethylated and mono-oxidized metabolites in rats and dogs. (R)-ketamine is primarily excreted via bile, accounting for 3.613% of the dose within 72 h, significantly higher than in feces (0.327%) or urine (0.030%). The main elimination pathway may be metabolic elimination, and eventually excreted in the form of metabolites. The predicted human plasma total clearance of 29.93 mL/min/kg is close to reported value.ConclusionThe preclinical pharmacokinetic characteristics of (R)-ketamine injection have been thoroughly investigated, and these findings can provide valuable information for predicting the first-in-human dose and designing Phase I clinical trials for (R)-ketamine injection.

The use of conventional opioids that act on μ-receptors is a recognized care agent for moderate-to-severe acute treatment. However, recent attention has shifted to a new class of μ-receptor agonists which can selectively activate the G-protein pathway and thus have better efficacy and fewer side effects. Recently, YZJ-4729 was developed as a new G protein selective μ-opioid receptor agonist. And for its clinical trial investigation usage, a rapid LC-MS/MS method was established for the concurrent measurement of YZJ-4729 and its major metabolite M10 in human plasma. A step involving the precipitation of proteins was used for plasma sample preparation. The chromatography separation was done on a Poroshell 120 EC-C18 analytical column (2.1 × 50 mm, 2.7-μm, Agilent). Gradient elution was performed with 5.0 mM ammonium acetate (NH4Ac) and 0.1 % formic acid (FA) water solution as the mobile phase A and pure acetonitrile (ACN) as the mobile phase B. Detection occurred in the mode of positive ion electrospray ionization through multiple reaction monitoring using deuterium YZJ-4729 (d6-YZJ-4729) as the internal standard. The ionic transitions used were YZJ-4729: m/z 409.3 → 244.2; d6-YZJ-4729: m/z 415.3 → 244.2; M10: m/z 425.3 → 260.2;). The method showed excellent linearity across the ranges of 0.500 to 500 ng/mL for YZJ-4729 and 0.0500 to 50.0 ng/mL for M10. The method was utilized to assess the plasma concentrations of YZJ-4729 and M10 in healthy volunteers after a 30-min intravenous infusion in the phase I clinical study, and the clinical pharmacokinetic profiles of YZJ-4729 and M10 were described.

Approximately 25% of breast cancer patients with HER2 overexpression tend to have a high risk of disease progression and death. Various HER2-targeting therapies have been approved for treatment. Recently, a novel antibody-drug conjugate, SHR-A1201, is being researched and developed. For the pharmacokinetic study of SHRA1201, suitable bioanalytical methods are needed for quantifying unconjugated cytotoxin, cytotoxin-conjugated antibodies and total antibodies. In this research, bioanalytical methods involving a highly sensitive LC-MS/MS assay for unconjugated cytotoxic payload DM1 in human plasma, ELISA strategies for DM1-conjugated trastuzumab and total trastuzumab in human serum were developed, validated and successfully applied to a phase I dose-escalation pharmacokinetic study of SHR-A1201. The pharmacokinetic properties and exposure-to-dose proportionality was evaluated for SHR-A1201. According to the bioanalytical method validation guidance, the bioanalytical methods were fully validated and the validation results met the acceptance criteria. The nonspecific binding of DM1 and dimer was avoided for the LC-MS/MS assay. In the dose-escalation pharmacokinetic study of SHR-A1201, a potential dose-proportional pharmacokinetics was observed over the dose from 1.2 mg/kg to 4.8 mg/kg. The validated bioanalytical strategies are robust and reproducible and these bioanalytical methods will contribute to better understanding of the pharmacokinetic properties of SHR-A1201.

Aims: Youkenafil is a novel selective phosphodiesterase type 5 inhibitor to treat erectile dysfunction. Since it was mainly metabolized through cytochrome P450 3A4/5 (CYP3A4/5) in vitro, the effects of itraconazole and rifampicin (potent CYP3A4/5 inhibitor and inducer, respectively) on the pharmacokinetics of youkenafil and its main metabolite (M1) were investigated in two clinical studies. Methods: Each study enrolled thirty healthy male subjects. In study 1, subjects were given a single dose of youkenafil (50 mg on Days 1 and 13) and multiple doses of itraconazole (200 mg once daily from Days 6 to 14). In study 2, subjects were given a single dose of youkenafil (100 mg on Days 1 and 20) and multiple doses of rifampicin (600 mg once daily from Days 6 to 20). Results: Itraconazole significantly increased the systemic exposure to youkenafil and M1. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) for the AUC0-t, AUC0-∞ and Cmax of youkenafil were 1198.58% (900.33%–1595.63%), 1162.54% (874.69%–1545.11%) and 632.17% (500.40%–798.64%), respectively. Conversely, rifampicin significantly decreased the systemic exposure to youkenafil but had a slight effect on M1. The GMRs (90% CI) for the AUC0-t, AUC0-∞ and Cmax of youkenafil were 1.72% (1.27%–2.33%), 1.80% (1.33%–2.43%) and 1.77% (1.27%–2.47%), respectively. All subjects tolerated well in both studies. Conclusion: Itraconazole increased youkenafil AUC and Cmax by 12- and 6-fold, respectively. Rifampicin decreased youkenafil AUC and Cmax both by about 98%. Therefore, combined administration of youkenafil with potent inhibitors or inducers of CYP3A4/5 should be avoided or carefully monitored.

Objective: YZJ-4729 is a novel G protein-biased μ-opioid receptor agonist for the treatment of acute pain in adult patients who require intravenous opioid analgesic therapy. The aim of this study was to assess the pharmacokinetics, metabolite profiling, safety and tolerability of YZJ-4729 in healthy Chinese subjects following the single intravenous doses ranged from 0.2 mg to 6 mg.Methods: This single-center, randomized, double-blind, placebo-controlled clinical study was conducted in 54 healthy male and female Chinese subjects after single ascending doses of YZJ-4729 tartrate (0.2, 0.5, 1.5, 3, 4.5, and 6 mg). Subjects in each cohort were assigned randomly to receive a single intravenous dose of YZJ-4729 tartrate injection or placebo at a ratio of 4:1. Pharmacokinetic characteristics, metabolite profiling, safety and tolerability profiles of the study drug were evaluated.Results: Overall, YZJ-4729 was safe and well tolerated in healthy Chinese subjects. The study drug reached peak plasma concentrations nearly at the end of the infusion. After administration, YZJ-4729 was eliminated rapidly with a terminal elimination half-life of 0.862–2.50 h, and excreted little in human excreta. The maximum drug concentration and area under the plasma concentration-time curve increased with dose escalation across the entire dose range. YZJ-4729 experienced extensive metabolism in human body. A total of 19 metabolites were identified and the characteristic metabolic pathways involved hydroxylation, ketone formation, N-dealkylation and glucuronide conjugation. Metabolite M10 was the most abundant circulating metabolite, and represented over 10% of total drug-related systemic exposure. Further PK and safety evaluation of M10 was necessary.Conclusion: The clinical study results laid a foundation for the further clinical studies of YZJ-4729 in patients.Clinical Trial Registration:http://www.chinadrugtrials.org.cn, identifier CTR20222574.

In biosensing analysis, the activity of enzyme systems is limited by their fragility, and substrates catalyzed by monoenzymes tend to undergo spontaneous decomposition during ineffective mass transfer processes. In this study, we propose a novel strategy to encapsulate the glucose oxidase and horseradish peroxidase (GOx&HRP) cascade catalytic system within the hydrophilic zeolite imidazole framework ZIF-90. By leveraging the specific pore structure of ZIF-90, we effectively immobilized GOx and HRP molecules in their three-dimensional conformations, which improved the catalytic activity of the encapsulated enzymes compared with that of free GOx and HRP in various harsh environments. Additionally, our strategy reduced the occurrence of ineffective mass transfer and enhanced the sensitivity of the biosensor through an enzyme cascade system. When this biosensor was applied to serum samples containing complex biological matrices, the degradation of GOx&HRP by various proteases and the surface adsorption of diverse biomolecules were effectively prevented, thereby generating stable and reliable signals of glucose levels. The sensor shows remarkable sensitivity and selectivity for determining glucose concentrations ranging from 0 to 2.5 mu g ml-1, with a detection limit as low as 0.034 mu g ml-1. Furthermore, we developed a paper-based colorimetric sensor utilizing GOx&HRP@ZIF-90 integrated with a smartphone platform for the visual detection of blood glucose.

The investigation of peptide drugs has become essential in the development of innovative medications for hypertension. In this study, a sensitive high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed to determine the plasma concentration and stability of the antihypertensive peptide FR-6 in rats. An isotopically labeled peptide (with an unchanged sequence) was utilized as an internal standard (IS) for validation purposes. Subsequently, this assay was employed to examine the pharmacokinetics of different administration methods (tail vein and gavage) in Sprague Dawley (SD) rats. Extracted plasma samples underwent sample preparation through methanol protein precipitation, followed by elution of FR-6 on Wondasil C18 Superb column (4.6 × 150 mm, 5 μm), using a mobile phase consisting of formic acid (0.1%) in water (A) and formic acid (0.125%)-ammonium formate (2 mM) in methanol (B). Ion pairs corresponding to FR-6 and IS were monitored via multiple reaction monitoring (MRM) under positive ion mode: m/z 400.7 → 285.1 for FR-6 and m/z 406.1 → 295.1 for IS detection respectively. The method exhibited excellent linearity with respect to FR-6 concentrations. In addition, the inter-day and intra-day precision were 0.61–6.85% and 1.76–11.75%; the inter-day and intra-day accuracy were −7.28–0.13% and −7.20–2.28%, respectively. In conclusion, the matrix effect, extraction recovery, and stability data were validated according to FDA recommended acceptance criteria for bioanalytical methods. This validated method serves as a reliable tool for determining the concentration of antihypertensive peptide FR-6, and has been successfully applied in pharmacokinetic studies involving rats.

101BHG-D01 is a novel, long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD) and rhinorrhea in rhinitis. To support its clinical study, several liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the quantification of 101BHG-D01 and its main metabolite M6 in human plasma, urine and feces were developed. The plasma samples were prepared by protein precipitation, and the urine and fecal homogenate samples were pretreated by direct dilution, respectively. The chromatographic separation was performed on an Agilent InfinityLab Poroshell 120 C18 column with 0.1% formic acid and 10.0 mM ammonium acetate buffer solution in water and methanol as the mobile phase. The MS/MS analysis was performed by using multiple reaction monitoring (MRM) under a positive ion electrospray ionization mode. The methods were validated with regards to selectivity, linearity, lower limit of quantitation (LLOQ), accuracy and precision, matrix effect, extraction recovery, dilution integrity, batch size, carryover and stability. The calibration ranges were as follows: 1.00-800 pg/mL for 101BHG-D01 and 1.00-20.0 pg/mL for M6 in plasma; 0.0500-20.0 ng/mL for 101BHG-D01 and M6 in urine; 0.400-400 ng/mL for 101BHG-D01 and 0.100-100 ng/mL for M6 in feces. There was no endogenous or cross interference observed at the retention time of the analytes and internal standard in various biological matrices. Across these matrices, for the lower limit of quantitation quality control (LLOQ QC) samples, the intra- and inter-batch coefficients of variation were within 15.7%. For other QC samples, the intra- and inter-batch coefficients of variation were within 8.9%. The intra- and inter-batch accuracy deviations for all QC samples were within the range of - 6.2-12.0%. No significant matrix effect was observed from the matrices. The extraction recoveries of these methods at different concentrations were consistent and reproducible. The analytes were stable in different matrices under various storage conditions. The other bioanalytical parameters were also fully validated and met the criteria given in the FDA guidance. These methods were successfully applied to a clinical study in healthy Chinese subjects after a single dose administration of 101BHG-D01 inhalation aerosol. After inhalation, 101BHG-D01 was absorbed into plasma rapidly with the time to reach the maximum drug concentration (Tmax) of 5 min and eliminated slowly with a half-life time about 30 h. The cumulative urinary and fecal excretion rates revealed 101BHG-D01 was mainly excreted in feces, rather than urine. The pharmacokinetic results of the study drug laid a foundation for its further clinical development.

动物源医疗器械作为应用广泛的医疗器械产品,应不断完善其评价技术和方法,提升质量评价标准,以促进产业的健康发展.临床使用过程中,动物源医疗器械产品产生的可沥滤物会不同程度地对人体产生危害.因此,总结概括动物源医疗器械可沥滤物的研究进展,对于动物源医疗器械产品质量控制具有重要意义.本文介绍了动物源医疗器械可沥滤物的监管现状,对不同来源的可沥滤物进行了分类分析,并总结概括了相关浸提液的制备方法、可沥滤物的检测方法、可沥滤物允许限量的确定方法.最后,对动物源医疗器械领域的研究和质量评价现状进行了概括和展望.

Background:: 101BHG-D01, a novel long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD), is undergoing Phase Ib clinical trial in patients and has shown its potential efficacy. Its preparation method and medical use thereof have been patented in the United States (Patent No.US9751875B2). Objective:: In this study, the pharmacokinetics, mass balance, tissue distribution and metabolism of radioactive 101BHG-D01 were investigated in rats after an intravenous dose of 1 mg/kg [14C]101BHG-D01 (100 μCi/kg). Methods:: Radioactivity in rat plasma, urine, feces, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling and identification were conducted by UHPLC-β-RAM and UHPLC-Q-Exactive Plus MS. Results:: The total radioactivity of the study drug in rat plasma rapidly declined with an average terminal elimination half-life of 0.35 h. The radioactivity in most tissues reached the maximum concentration at 0.25 h post-- dosing. The radioactivity mainly concentrated in the kidney and pancreas. The drug-related substances tended to be distributed into the blood cells in the circulation. At 168 h post dosing, the mean recovery of the total radioactivity in urine and feces was 78.82%. Fecal excretion was the major excretion route, accounting for approximately 61% of the radioactive dose. The study drug was metabolized extensively, and a total of 17 metabolites were identified in rat plasma, urine, and feces. The major metabolic pathways involved oxidation, oxidation and dehydrogenation, and O-dephenylation. Conclusion:: In conclusion, the study results are useful for better understanding the pharmacokinetic profiles of 101BHG-D01 and provide a robust foundation for subsequent clinical studies.

Ferric maltol has been used as an oral drug for iron deficiency. This study developed and fully validated the novel HPLC-MS/MS methods to determine maltol and maltol glucuronide simultaneously in plasma and urine. The protein precipitation was performed by addition of acetonitrile in the plasma samples. The dilution was per-formed for the urine samples to reach the suitable concentrations for injection. The multiple reaction monitoring (MRM) with an electrospray ionization (ESI) positive ion detection mode was used for the quantification. The maltol concentration linear ranges were 6.00-150 ng/mL and 0.100-10.0 & mu;g/mL for the plasma and urine samples, respectively. The maltol glucuronide concentration linear ranges were 50.0-15000 ng/mL and 2.00-2000 & mu;g/mL for the plasma and urine samples, respectively. These methods were applied to a single dose clinical study at a dose of 60 mg ferric maltol capsule in the patients with iron deficiency. The half-lives of maltol and maltol glucuronide were 0.90 & PLUSMN; 0.40 h and 1.02 & PLUSMN; 0.25 h in the iron deficiency patients, respectively. 39.52 & PLUSMN; 7.11 % maltol were excreted in urine in the form of maltol glucuronide.

Pivmecillinam, the ester of biologically active antibiotic mecillinam, is an effective oral preparation to treat urinary tract infections. To study pharmacokinetics in humans, LC-MS/MS methods were developed to quantify pivmecillinam and mecillinam in human plasma, respectively. Cephalexin as internal standards, analytes were separated on Ultimate® XB-C18 columns after protein precipitation by acetonitrile. The mobile phase was composed of water containing 0.1% formic acid and methanol. The multiple reactions monitoring transitions of m/z 440.2→167.1, 326.1→167.1 and 348.1→158.1 were selected to inspect pivmecillinam, mecillinam and the internal standards in positive ion mode. No apparent matrix effect was perceived. Linearities were obtained over calibration ranges of 0.0500-12.0 and 10.0-15000 ng/mL, respectively. The intra-day precisions were below 5.5%, the inter-day precisions were below 6.1%, and accuracies got within -8.1% to 13.0%. Stability tests were conducted and an acidification step was explored to enhance the stability of pivmecillinam and mecillinam. Further stability was validated under various storage and processing conditions. Both methods were applied to a pharmacokinetic study of pivmecillinam and mecillinam after oral administration of 400 mg pivmecillinam hydrochloride tablets in healthy Chinese subjects. This article is protected by copyright. All rights reserved.

药物色谱分析实验是药学专业学生一门重要的基础性实验课程,以往的实验教学模式缺乏有效的教学手段,难以满足企业对具有优秀科学素养药学人才的需求.分析传统药物色谱分析课程教学模式中存在的问题,探讨改革教学模式的必要性,构建以"APP教学平台""虚拟仿真实验教学平台"和"开放式实验教学平台"为基础的新型实验教学模式,从而培养学生的创新意识,提高学生的实践能力.

Lubiprostone, a derivative of prostaglandin E1, is the first chemical-type constipation treatment approved by FDA. Lubiprostone has low systemic exposure after oral administration. Therefore, it is recommended that 15-hydroxylubiprostone, which is a dominant active metabolite of lubiprostone, be used as the pharmacokinetic evaluation indicator. Due to the microdosage of the lubiprostone capsules, it is difficult to develop a highly sensitive bioanalytical method for 15-hydroxylubiprostone.In this study, a highly sensitive and selective liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method has been established and fully validated for the quantification of 15-hydroxylubiprostone in human plasma, and the validated bioanalytical method has been applied to a pharmacokinetic study of lubiprostone capsules successfully.The pharmacokinetics of 15-hydroxylubiprostone were observed after fed administration in healthy Chinese volunteers. The Cmax and AUC0-t were 75.8 ± 57.6 pg/mL and 222 ± 68.0 pg·h/mL for 15-hydroxylubiprostone.This study investigated the pharmacokinetic properties of 15-hydroxylubiprostone under fed conditions in healthy Chinese volunteers and would provide clinical guidance for the application and further development of lubiprostone capsules.