Effect of High-Fat Meal on the Pharmacokinetics and Safety of Valsartan/Amlodipine Fixed Dose Combination Tablets in Healthy Subjects.

Background: The objective of this study was to evaluate the effect of a high-fat meal on the pharmacokinetics and safety of 80/5 mg valsartan/amlodipine tablets in healthy subjects. Subjects and Methods: These results were derived from a bioequivalence trial where subjects were randomly assigned to take valsartan/amlodipine 80/5mg under fed conditions or after a high-fat meal contained 978.6 kilocalories (54.6% from fat). The blood samples were collected and plasma concentrations of valsartan/amlodipine were measured using high-performance liquid chromatography-mass spectrometry. The non-compartmental module of Phoenix WinNonlin Version 8.2 was used to calculate pharmacokinetic parameters. The BE module of WinNonLin was used to analyze the statistics of the maximum plasma concentration (Cmax), the area under the concentration-time curve from zero to the last quantifiable time point (AUC0-t), and the area under the concentration-time curve from zero to infinity(AUC0-∞) in plasma. 88 healthy subjects were enrolled and divided into in a fasted group and a fed group. Results: The Cmax, AUC0-t, and AUC0-∞ of valsartan in plasma under fed conditions were 51%, 56%, and 57% lower, respectively, than those under fasted conditions, and the 90% confidence interval (90% CI) were outside the 80.00-125.00% range. All the pharmacokinetic parameters for amlodipine under fed conditions were similar to those observed under fasted conditions, and the 90% CIs were within the 80.00-125.00% range. The incidence of treatment emergent adverse events (TEAE) was similar between the fasted group and the fed group, while adverse drug reaction (ADR) was more frequent in the fasted group which may be related to the higher blood concentrations of valsartan, but all were mild. Conclusion: The result indicated that the high-fat meal had a significant effect on the pharmacokinetics of valsartan, but no effect on amlodipine. All treatments were safe and well tolerated in healthy subjects under fed and fasted conditions.

Effect of a High-Fat Diet on the Pharmacokinetics and Safety of Rivaroxaban in Healthy Chinese Subjects.

The effects of food on the pharmacokinetics (PKs) and safety of 10-mg rivaroxaban tablets in healthy Chinese subjects were investigated from 1 bioequivalence trial. The bioequivalence trial was designed as randomized, open-label, 2-sequence, 4-period crossover under both fasted and fed conditions. A total of 56 healthy subjects were enrolled, 62.5% were male. These subjects received a single oral 10-mg dose of rivaroxaban with a 7-day washout between 4 periods. Serial PK samples were collected and plasma concentrations were analyzed using validated high-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental methods. The BE module of WinNonLin was used for statistical analysis of the maximum concentration (Cmax ), the area under the concentration-time curve from zero to the final measurable concentration (AUC0-t ), and the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) of rivaroxaban in plasma. Compared with the fasted state, the Cmax , AUC0-t , and AUC0-∞ of rivaroxaban significantly increased by 47%, 28%, and 26%, respectively, with oral administration of rivaroxaban 10 mg in the fed state. The incidence of adverse events (AEs) was similar between the fasted and fed states, and no serious AEs were observed. Food significantly increased the exposure to rivaroxaban 10 mg in Chinese subjects.

In vivo evaluation of the pharmacokinetic interactions between almonertinib and rivaroxaban, almonertinib and apixaban.

Background: Almonertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is commonly used as a first-line treatment for non-small cell lung cancer (NSCLC) patients with EGFR T790M mutations. Rivaroxaban and apixaban are a selective, direct factor Xa inhibitor used to treat venous thromboembolism (VTE), which is a frequent complication of NSCLC. Rivaroxaban and apixaban are substrates of CYP3A4, P-gp and BCRP, whereas almonertinib is an inhibitor of P-gp and BCRP. Rivaroxaban or apixaban are often prescribed together with almonertinib in NSCLC patients, but clear information on pharmacokinetic drug interaction is lacking. Therefore, this study aimed to unravel the extent of interactions between almonertinib-rivaroxaban and almonertinib apixaban in rats, and whether the pharmacokinetic interaction can be mitigated by rivaroxaban and apixaban dose adjustment. Methods: Rats were divided into ten groups (n = 6) that received rivaroxaban (2 mg/kg) (group 1), apixaban (0.5 mg/kg) (group 2), almonertinib (15 mg/kg) (group 3, group 4), almonertinib with rivaroxaban (2 mg/kg) (group 5), almonertinib with rivaroxaban (1 mg/kg) (group 6), almonertinib with apixaban (0.5 mg/kg) (group 7), almonertinib with apixaban (0.25 mg/kg) (group 8), rivaroxaban (2 mg/kg) with almonertinib (group 9), apixaban (0.5 mg/kg) with almonertinib (group 10). The concentrations of drugs were determined by an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The levels of messenger RNA were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Results and Discussion: The results indicate that almonertinib increased the Cmax and AUC0-t of 2 mg/kg rivaroxaban by 3.30 and 3.60-fold, 1 mg/kg rivaroxaban by 1.28 and 1.90-fold. Almonertinib increased the Cmax and AUC0-t of 0.5 mg/kg apixaban by 2.69 and 2.87-fold, 0.25 mg/kg apixaban by 2.19 and 2.06-fold. In addition, rivaroxaban also increased systemic exposure to almonertinib. The results of qRT-PCR showed that almonertinib reduced the expression of Cyp3a1 in liver and intestine, and Abcb1a, Abcg2 in intestine and kidney. The pharmacokinetic results suggest that it is important to take special care of the interactions of these drugs in clinical applications.

Bioequivalence Study of Vortioxetine Hydrobromide Tablets in Healthy Chinese Subjects Under Fasting and Fed Conditions.

Objective: This study compared the pharmacokinetic and safety profiles of generic and original vortioxetine hydrobromide tablets under fasting and fed conditions, and evaluated the bioequivalence of two vortioxetine formulations to obtain sufficient evidence for abbreviated new drug application. Methods: A randomized, open-label, two-formulation, single-dose, two-period crossover bioequivalence study was conducted under fasting and fed conditions (n = 32 per study). Eligible healthy Chinese subjects received a single 10-mg dose of the test or reference vortioxetine hydrobromide tablet, followed by a 28-day washout interval between periods. Serial blood samples were collected up to 72 h after administration in each period, and the plasma concentrations of vortioxetine were detected using a validated method. The primary pharmacokinetic (PK) parameters were calculated using the non-compartmental method. The geometric mean ratios for the PK parameters of the test drug to the reference drug and the corresponding 90% confidence intervals were acquired for bioequivalence analysis. A safety evaluation was performed throughout the study. Results: Under fasting and fed conditions, the PK parameters of the test drug were similar to those of the reference drug. The 90% confidence intervals (CIs) of the geometric mean ratios of the test to reference formulations were 96.44-105.81% for peak concentration (Cmax), 97.94-105.05% for the area under the curve truncated at 72 hours (AUC0-72 h) under fasting conditions, 93.92-104.15% for Cmax, and 96.67-102.55% for AUC0-72 h under fed conditions, all of which were within the accepted bioequivalence range of 80.00-125.00%. Both the test and reference formulations were well-tolerated, and no serious adverse events related to the study drug were reported during the study. Conclusion: The PK bioequivalence of the test and reference vortioxetine hydrobromide tablets in healthy Chinese subjects was established under fasting and fed conditions, which met the predetermined regulatory criteria. Both formulations were safe and well tolerated.

Pharmacokinetics and safety of highly variable valsartan in single-pill combination with amlodipine versus its generic formulation: a randomized, three-cycle, three-sequence, partially replicated crossover phase I bioequivalence clinical trial.

Valsartan/amlodipine (I) is a single-pill combination (SPC) of an angiotensin II receptor blocker (ARB) and a calcium channel blocker (CCB) for treating hypertension. A clinical trial was performed to demonstrate that the test and reference valsartan/amlodipine formulations were bioequivalent under fasting and postprandial conditions. Participants were randomly divided into three sequences at a ratio of 1:1:1 for three-cycle, reference formulation replicated, crossover administration. The average bioequivalence (ABE) and reference-scaled average bioequivalence (RSABE) methods were used to evaluate BE using the main pharmacokinetic (PK) parameters. Overall, 45 eligible participants were enrolled in the postprandial trial, which was consistent with the fasting trial. For valsartan, the RSABE method was used to evaluate the BE of Cmax, while the ABE method was applied to evaluate the BE of AUC0-t and AUC0-∞. Both point estimates and 95% upper confidence bound met the BE criteria. For amlodipine, the ABE method was performed, and the 90% confidence intervals of the geometric mean ratios (GMR) for Cmax and AUC0-72 h were all within 80%-125%, with the BE criteria being met. Therefore, the two formulations are bioequivalent and have similar safety profiles in healthy Chinese subjects. Clinical trial registration: [http://www.chinadrugtrials.org.cn/index.html], identifier [CTR20210214].

Determination of vericiguat in rat plasma by UPLC-MS/MS and its application to drug interaction.

Vericiguat (VER) is a novel soluble guanylate cyclase stimulator treating symptomatic chronic heart failure (HF), and it is a substrate of both transporters P-glycoprotein and breast cancer resistance protein (BCRP). Astragaloside IV (ASIV) is the main active ingredient in Radix Astragali (Huangqi), a traditional Chinese medicine widely used for HF treatment in China. ASIV's effect on the protein expression of P-glycoprotein and BCRP has been observed, its impact on VER metabolism remain uncertain. In the present study, male Sprague-Dawley rats were administered with 20 mg/kg ASIV and 1 mg/kg VER to study their pharmacokinetics. Blood samples were subject to liquid-liquid extraction, and riociguat was employed as the internal standard (IS). The analytical method involved a C18 column (XSelect® HSS T3 column, 2.1 × 100 mm, 2.5 µm) with a mobile phase of 0.1% formic acid and acetonitrile for gradient elution. The flow rate of the mobile phase was set at 0.2 mL/min, and 5 µL of the sample was used for analysis. The positive ion multi-response monitoring mode was utilized with a transition of m/z 427.4→109.1 for VER and m/z 423.3→109.1 for the IS. The method exhibited good linearity within the concentration range of 0.1 to 300 ng/mL (r = 0.9987), and all the validation processes were conducted in accordance with the requirements of biological analysis. The pharmacokinetic results revealed that ASIV did not significantly alter the main parameters of VER, except for Cmax, which decreased by 33.2% (P < 0.05). Overall, our study successfully established a selective, sensitive and repeatable ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis for detecting VER in rat plasma.

Quantification of sedative-hypnotics in human urine and plasma via polystyrene-based solid phase extraction-LC-MS/MS analysis.

Owing to the adverse effects of the overuse of common sedative-hypnotics on human health, the development of an efficient analytical method for the detection of drugs in clinical emergencies and forensic science is significant. Although conventional analytical methods, such as immunoassay, liquid chromatography (LC), gas chromatography, and mass spectrometry (MS) are reliable, they exhibit drawbacks such low-throughput screening and high costs. Thus, in this study, we developed a novel high-throughput method consisting of a polystyrene-based solid phase extraction (SPE) and an LC with tandem MS analysis for the detection of drugs in biological samples and investigated its precision and reliability via the detection of twelve sedative-hypnotics in human urine and plasma samples. Good linear relationship (r ≥ 0.99) were achieved within the concentration range of 0.1-20 ng/mL for the 12 analytes in urine samples. Whereas, in the plasma samples, the correlation coefficient was greater than 0.99 in the concentration range 1-100 ng/mL for lorazepam and clonazepam and in the range 0.5-100 ng/mL for the remaining analytes. The intra- and inter-day precision, autosampler and freeze-thaw stabilities, and lower limit of quantitation (LLOQ) for all twelve analytes in the urine and plasma samples were favorable. Furthermore, sedative-hypnotics were detected in clinical samples obtained from the Hebei General Hospital using this method. These results indicated that the analytical method proposed in this study can be effectively applied in toxicology screening and drug abuse monitoring.The method developed in this study could be applied in clinical and forensic toxicology laboratories for sedative-hypnotic drug screening, providing support for drug abuse monitoring and clinical diagnosis.

Anti­PD1 therapy­associated distal renal tubular acidosis: A case report.

Distal renal tubular acidosis (RTA) is a rare adverse reaction to immune checkpoint inhibitors, which only occurs in a small number of cases. To the best of our knowledge, distal RTA caused by sintilimab, a programmed cell death protein 1 (PD-1) inhibitor, has not been previously reported. In the present study, the case of a 62-year-old man with metastatic cardiac carcinoma treated with sintilimab anti-PD-1 therapy was reported. After the fourth administration of sintilimab, the treatment course was interrupted by metabolic hyperchloraemic acidosis with hypokalaemia. Following urine and blood tests, immunotherapy-induced distal RTA was suspected. Treatment with sintilimab and chemotherapy was stopped, and treatment with sodium bicarbonate and potassium citrate was started, which resulted in an adequate response. The present study provides the first case of distal RTA secondary to sintilimab treatment.

In vivo assessment of the pharmacokinetic interactions between donafenib and dapagliflozin, donafenib and canagliflozin in rats.

Donafenib (DONA), a deuterium derivative of sorafenib, is used for advanced hepatocellular carcinoma (HCC). Dapagliflozin (DAPA) and canagliflozin (CANA) are sodium-glucose co-transporter 2 (SGLT2) inhibitors used for T2DM, which is frequently comorbid with HCC. Three drugs are substrates of UGT1A9 isoenzyme. This study aimed to evaluate donafenib-dapagliflozin and donafenib-canagliflozin pharmacokinetic interactions and explore the potential mechanisms. Rats were divided into seven groups (n = 6) that received donafenib (1), dapagliflozin (2), canagliflozin (3), dapagliflozin and donafenib (4), canagliflozin and donafenib (5), donafenib and dapagliflozin (6), donafenib and canagliflozin (7). The concentrations of drugs were determined by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The messenger RNA (mRNA) expressions were measured by quantitative RT-PCR. Multiple doses of dapagliflozin caused donafenib maximum plasma concentration (Cmax) to increase 37.01%. Canagliflozin increased donafenib Cmax 1.77-fold and the area under the plasma concentration-time curves (AUC0-t and AUCinf) 1.39- and 1.41-fold, respectively, while reducing the apparent clearance (CLz) 28.38%. Multiple doses of donafenib increased dapagliflozin AUC0-t 1.61-fold, AUCinf 1.77-fold, whereas its CLz reduced 40.50%. Furthermore, donafenib caused similar changes in canagliflozin pharmacokinetics. The PCR results demonstrated that dapagliflozin inhibited the mRNA expression of Ugt1a7 in liver and donafenib decreased the expression of Ugt1a7 mRNA in liver and intestine. Increased exposure to these drugs may be due to their metabolism inhibition mediated by Ugt1a7. These pharmacokinetic interactions observed in this study may be of clinical significance, which may help adjust dose properly and avoid toxicity effects in patients with HCC and T2DM.

Evidence-based guideline for the prevention and management of perioperative infection.

BACKGROUND: We have updated the guideline for preventing and managing perioperative infection in China, given the global issues with antimicrobial resistance and the need to optimize antimicrobial usage and improve hospital infection control levels. METHODS: We conducted a comprehensive evaluation of the evidence for prevention and management of perioperative infection, based on the concepts of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The strength of recommendations was graded and voted using the Delphi method and the nominal group technique. Revisions were made to the guidelines in response to feedback from the experts. RESULTS: There were 17 questions prepared, for which 37 recommendations were made. According to the GRADE system, we evaluated the body of evidence for each clinical question. Based on the meta-analysis results, recommendations were graded using the Delphi method to generate useful information. CONCLUSIONS: This guideline provides evidence to perioperative antimicrobial prophylaxis that increased the rational use of prophylactic antimicrobial use, with substantial improvement in the risk-benefit trade-off.

Effects of voriconazole and fluconazole on the pharmacokinetics of almonertinib in rats by UPLC-MS/MS.

Almonertinib was included in the first-line treatment of non-small cell lung cancer with EGFR T790M mutations by the Chinese Society of Clinical Oncology in 2021. Considering that immunocompromised lung cancer patients are prone to opportunistic fungal infections, and most triazole antifungal drugs are moderate or strong inhibitors of CYP3A4, this study was conducted to develop and validate an accurate and rapid ultra-performance liquid chromatography tandem mass spectrometry method for quantifying almonertinib in plasma and for investigating the pharmacokinetic changes of almonertinib caused by voriconazole and fluconazole in rats. After liquid-liquid extraction with tert-butyl methyl ether, an XSelect HSS T3 column (2.1 × 100 mm, 2.5 µm, Waters) was used for the chromatographic separation of almonertinib and sorafenib-D3 (internal standard). The analytes were detected using an AB Sciex Triple Quad 5,500 mass spectrometer in the positive ionization mode. The method exhibited great linearity (0.5-200 ng/ml, r > 0.997) and stability under the established experimental conditions. All validation experiments were in accordance with the guidelines, and the results were all within the acceptable limits. This method was successfully applied to the researches of pharmacokinetics and drug interactions for almonertinib in rats. Voriconazole and fluconazole significantly altered the pharmacokinetic profiles of almonertinib and increased the systemic exposure of almonertinib in rats to different degrees, but further human trials should be conducted to validate the results.

Acute liver injury induced by drug interaction between dacomitinib and metoprolol due to the inhibition of CYP2D6 by dacomitinib.

INTRODUCTION: In recent years, oral antineoplastic agents are commonly used in antitumor therapy. The interaction between drugs may affect the efficacy of drugs or lead to adverse reactions. We describe the case of a patient who presented acute liver injury, possibly induced by the concomitant use of metoprolol and dacomitinib. CASE REPORT: A 62-year-old male patient with non-small cell lung cancer was admitted for anti-cancer treatment. He regularly took metoprolol tartrate 12.5 mg, 2/day for hypertension. He was treated with dacomitinib according to EGFR Exon21 L858R positive. After 3 days of dacomitinib, the patient's alanine aminotransferase (ALT) and glutathione aminotransferase (AST) increased, and the heart rate and systolic blood pressure of the patient decreased significantly. The patient was diagnosed with acute liver injury. MANAGEMENT AND OUTCOMES: Dacomitinib was discontinued and glutathione, magnesium isoglycyrrhizinate were given to treat acute liver injury. Two days after discontinued dacomitinib, the patient's heart rate increased, but the ALT and AST of the patient elevated again. Metoprolol tartrate was subsequently discontinued and the ALT and AST gradually decreased and the patient discharged from the hospital eight days later with his liver function improved. DISCUSSION: To our knowledge, this is the first case in the literature of acute liver injury possibly induced by the interaction between metoprolol and dacomitinib. The interaction most likely arose because dacomitinib is a CYP2D6 strong inhibitor and could therefore impair the metabolism of metoprolol (a CYP2D6 substrate) and increase its serum concentration. Therefore, hepatic function should be carefully monitored in patients treated with dacomitinib and metoprolol and other inhibitors or inducers of CYP2D6.

Development of UPLC-MS/MS Method to Study the Pharmacokinetic Interaction between Sorafenib and Dapagliflozin in Rats.

Sorafenib (SOR), an inhibitor of multiple kinases, is a classic targeted drug for advanced hepatocellular carcinoma (HCC) which often coexists with type 2 diabetes mellitus (T2DM). Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor (SGLT2i), is widely used in patients with T2DM. Notably, co-administration of SOR with DAPA is common in clinical settings. Uridine diphosphate-glucuronosyltransferase family 1 member A9 (UGT1A9) is involved in the metabolism of SOR and dapagliflozin (DAPA), and SOR is the inhibitor of UGT1A1 and UGT1A9 (in vitro). Therefore, changes in UGT1A9 activity caused by SOR may lead to pharmacokinetic interactions between the two drugs. The objective of the current study was to develop an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of SOR and DAPA in plasma and to evaluate the effect of the co-administration of SOR and DAPA on their individual pharmacokinetic properties and the mechanism involved. The rats were divided into four groups: SOR (100 mg/kg) alone and co-administered with DAPA (1 mg/kg) for seven days, and DAPA (1 mg/kg) alone and co-administered with SOR (100 mg/kg) for seven days. Liquid-liquid extraction (LLE) was performed for plasma sample preparation, and the chromatographic separation was conducted on Waters XSelect HSS T3 column with a gradient elution of 0.1% formic acid and 5 mM ammonium acetate (Phase A) and acetonitrile (Phase B). The levels of Ugt1a7 messenger RNA (mRNA) were determined in rat liver and intestine using quantitative real-time polymerase chain reaction (qRT-PCR). The method was successfully applied to the study of pharmacokinetic interactions. DAPA caused a significant decrease in the maximum plasma concentrations (Cmax) and the area under the plasma concentration-time curves (AUC0-t) of SOR by 41.6% and 50.5%, respectively, while the apparent volume of distribution (Vz/F) and apparent clearance (CLz/F) significantly increased 2.85- and 1.98-fold, respectively. When co-administering DAPA with SOR, the AUC0-t and the elimination half-life (t1/2Z) of DAPA significantly increased 1.66- and 1.80-fold, respectively, whereas the CLz/F significantly decreased by 40%. Results from qRT-PCR showed that, compared with control, seven days of SOR pretreatment decreased Ugt1a7 expression in both liver and intestine tissue. In contrast, seven days of DAPA pretreatment decreased Ugt1a7 expression only in liver tissue. Therefore, pharmacokinetic interactions exist between long-term use of SOR with DAPA, and UGT1A9 may be the targets mediating the interaction. Active surveillance for the treatment outcomes and adverse reactions are required.

Pharmacokinetic Interactions between Canagliflozin and Sorafenib or Lenvatinib in Rats.

Hepatocellular carcinoma (HCC) and type 2 diabetes mellitus (T2DM) are common clinical conditions, and T2DM is an independent risk factor for HCC. Sorafenib and lenvatinib, two multi-targeted tyrosine kinase inhibitors, are first-line therapies for advanced HCC, while canagliflozin, a sodium-glucose co-transporter 2 inhibitor, is widely used in the treatment of T2DM. Here, we developed an ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of canagliflozin, sorafenib, and lenvatinib, and investigated the pharmacokinetic drug interactions between canagliflozin and sorafenib or lenvatinib in rats. The animals were randomly divided into five groups. Groups I-III were gavage administrated with sorafenib, lenvatinib, and canagliflozin, respectively. Group IV received sorafenib and canagliflozin; while Group V received lenvatinib and canagliflozin. The area under the plasma concentration-time curves (AUC) and maximum plasma concentrations (Cmax) of canagliflozin increased by 37.6% and 32.8%, respectively, while the apparent volume of distribution (Vz/F) and apparent clearance (CLz/F) of canagliflozin significantly decreased (30.6% and 28.6%, respectively) in the presence of sorafenib. Canagliflozin caused a significant increase in AUC and Cmax of lenvatinib by 28.9% and 36.2%, respectively, and a significant decrease in Vz/F and CLz/F of lenvatinib by 52.9% and 22.7%, respectively. In conclusion, drug interactions exist between canagliflozin and sorafenib or lenvatinib, and these findings provide a reference for the use of these drugs in patients with HCC and T2DM.

Determination of Osimertinib, Aumolertinib, and Furmonertinib in Human Plasma for Therapeutic Drug Monitoring by UPLC-MS/MS.

The third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib, aumolertinib, and furmonertinib represent a new treatment option for patients with EGFR p.Thr790 Met (T790 M)-mutated non-small cell lung cancer (NSCLC). Currently, there are no studies reporting the simultaneous quantification of these three drugs. A simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous quantitative determination of osimertinib, aumolertinib, and furmonertinib concentrations in human plasma, and it was applied for therapeutic drug monitoring (TDM). Plasma samples were processed using the protein precipitation method (acetonitrile). A positive ion monitoring mode was used for detecting analytes. D3-Sorafenib was utilized as the internal standard (IS), and the mobile phases were acetonitrile (containing 0.1% formic acid) and water with gradient elution on an XSelect HSS XP column (2.1 mm × 100.0 mm, 2.5 µm, Waters, Milford, MA, USA) at a flow rate of 0.5 mL·min-1. The method's selectivity, precision (coefficient of variation of intra-day and inter-day ≤ 6.1%), accuracy (95.8-105.2%), matrix effect (92.3-106.0%), extraction recovery, and stability results were acceptable according to the guidelines. The linear ranges were 5-500 ng·mL-1, 2-500 ng·mL-1, and 0.5-200 ng·mL-1 for osimertinib, aumolertinib, and furmonertinib, respectively. The results show that the method was sensitive, reliable, and simple and that it could be successfully applied to simultaneously determine the osimertinib, aumolertinib, and furmonertinib blood concentrations in patients. These findings support using the method for TDM, potentially reducing the incidence of dosing blindness and adverse effects due to empirical dosing and inter-patient differences.

Determination of atypical antipsychotics in human plasma by UPLC-UV with polystyrene nanofibers as a solid-phase extraction sorbent.

A novel extraction procedure was developed using polystyrene (PS) nanofibers as a solid-phase extraction sorbent to collect atypical antipsychotics (AAPs) from human plasma. The extraction targets were then monitored by ultra high performance liquid chromatography with an ultraviolet detector system. Parameters affecting extraction efficiency such as fiber packing amount, wash solution, and eluted solvent were investigated. Under optimized conditions, the linear range of seven AAPs was 1-50 µgmL-1 (R 2 > 0.996). Inter-day and intra-day relative standard deviations were less than 15.1%, and relative error varied from -17.1% to 12.0%. Furthermore, 50.5-79.3% extraction recoveries were obtained. The lower limit of quantification was 1 µg mL-1, and detection limit was 0.5 µg mL-1. The method developed in this study may be applied to simultaneous quantification of seven AAPs in human plasma due to its simplicity, selectivity, and efficiency.

Influence of schisantherin A on the pharmacokinetics of lenvatinib in rats and its potential mechanism.

Background: Lenvatinib (LEN) is approved as first-line therapy for advanced hepatocellular carcinoma (HCC). Schisantherin A (STA) can exert hepatoprotective and anti-tumor effects. The clinical combination of LEN and STA is very common, especially for patients with advanced HCC, but the effect of STA on the pharmacokinetics of LEN is unclear. This study aimed to investigate the effects of STA on the pharmacokinetics of LEN in rats and explore its potential mechanism. Methods: Male Sprague-Dawley (SD) rats were orally administered different doses of STA or vehicle control for 7 consecutive days, and 1.2 mg/kg of LEN was given on day 7. The messenger RNA (mRNA) and protein expression levels in the intestines and liver were investigated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. Results: It was revealed that STA increased the oral bioavailability of LEN. The area under the curve from time 0 to infinity (AUC0-∞) and maximum plasma concentration (Cmax) of LEN after co-administration with STA (20 mg/kg) increased by 54.3% (3,396.73±989.35 vs. 5,240.03±815.49 µg/L/h) and 54.8% (490.64±124.20 vs. 759.66±152.75 µg/L), respectively. The clearance decreased from 0.38±0.12 to 0.23±0.04 L/h/kg, and the apparent volume of distribution (Vz) decreased from 10.83±3.19 to 6.35±1.38 L/kg in the presence of 20 mg/kg STA. In addition, the expression of P-glycoprotein (P-gp) mRNA and protein in the intestines was markedly decreased. Conclusions: This study showed that STA increased the bioavailability of LEN, probably due to inhibition of P-gp in the intestine, thereby increasing systemic absorption of LEN. Thus, there is an interaction between the two drugs, and careful monitoring must be conducted when they are used in combination.

A Simple UPLC/MS-MS Method for Simultaneous Determination of Lenvatinib and Telmisartan in Rat Plasma, and Its Application to Pharmacokinetic Drug-Drug Interaction Study.

Lenvatinib is a multi-targeted tyrosine kinase inhibitor that inhibits tumor angiogenesis, but hypertension is the most common adverse reaction. Telmisartan is an angiotensin receptor blocker used to treat hypertension. In this study, a simple ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of lenvatinib and telmisartan, and it was applied to the pharmacokinetic drug interaction study. Plasma samples were treated with acetonitrile to precipitate protein. Water (containing 5 mM of ammonium acetate and 0.1% formic acid) and acetonitrile (0.1% formic acid) were used as the mobile phases to separate the analytes with gradient elution using a column XSelect HSS T3 (2.1 mm × 100 mm, 2.5 µm). Multiple reaction monitoring in the positive ion mode was used for quantification. The method was validated and the precision, accuracy, matrix effect, recovery, and stability of this method were reasonable. The determination of analytes was not interfered with by other substances in the blank plasma, and the calibration curves of lenvatinib and telmisartan were linear within the range of 0.2-1000 ng/mL and 0.1-500 ng/mL, respectively. The results indicate that lenvatinib decreased the systemic exposure of telmisartan. Potential drug interactions were observed between lenvatinib and telmisartan.

QiShenYiQi pills, a Chinese patent medicine, increase bioavailability of atorvastatin by inhibiting Mrp2 expression in rats.

CONTEXT: Atorvastatin (ATV) and QiShenYiQi pills (QSYQ), a Chinese patent medicine, are often co-prescribed to Chinese cardiovascular patients. The effects of QSYQ on the pharmacokinetics of ATV have not been studied. OBJECTIVE: We investigated the influence of QSYQ on the pharmacokinetics of ATV and its metabolites upon oral or intravenous administration of ATV to rats. MATERIALS AND METHODS: Sprague-Dawley rats (n = 5/group) were pre-treated with oral QSYQ (675 mg/kg) or vehicle control for 7 days and then orally administrated ATV (10 mg/kg) or intravenously administrated ATV (2 mg/kg). Serum concentrations of ATV and metabolites were determined by ultra-high performance liquid chromatography tandem mass spectrometry. Expression of metabolic enzymes and transporters in jejunum and ileum were measured by quantitative real-time PCR and Western blot. RESULTS: QSYQ resulted in an increase of AUC0-12 h of ATV from 226.67 ± 42.11 to 408.70 ± 161.75 ng/mL/h and of Cmax of ATV from 101.46 ± 26.18 to 198.00 ± 51.69 ng/mL and in an increased of para-hydroxy atorvastatin from 9.07 ± 6.20 to 23.10 ± 8.70 ng/mL in rats administered ATV orally. No change was observed in rats treated intravenously. The expression of multidrug resistance-associated protein 2 mRNA and protein decreased in ileum, and the mRNA of P-glycoprotein decreased in jejunum, though no change in protein expression was found. DISCUSSION AND CONCLUSIONS: QSYQ increased bioavailability of ATV administered orally through inhibiting the expression of Mrp2 in ileum. Clinicians should pay close attention to potential drug-drug interactions between ATV and QSYQ.

Integrating analysis of circular RNA and mRNA expression profiles in doxorubicin induced cardiotoxicity mice.

Doxorubicin (DOX)-induced cardiotoxicity impedes its clinical application, but the mechanisms have not been thoroughly elucidated. Based on circRNA and mRNA expression profiles, we illustrated RNA expression signature changes during DOX-induced cardiotoxicity; mechanism exploration and biomarkers screening were also conducted. Twelve mice were randomly divided into two groups, induction group was treated with doxorubicin, and the control group was given an equal quantity of saline. After the confirmation of myocardial injury in induction group, the heart tissues from both groups were isolated for RNA high-throughput sequencing. The expression profiles were compared between the two groups; a total of 295 mRNAs and 11 circRNAs were shown as biased expression in DOX-induced cardiotoxicity mouse hearts. The dysregulation of three circRNAs were validated by quantitative real-time PCR: mmu_circ_0015773, mmu_circ_0002106, and mmu_circ_001606. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the differentially expressed RNAs were performed; the results implied that DOX might cause cardiotoxicity by interfering hemoglobin-based oxygen delivery and DNA-associated signal pathways. We integrated the differential expressed mRNA and validated circRNAs by constructing a competing endogenous RNA (ceRNA) network, which indicated that the alteration of the three circRNAs could activate apoptosis process of myocardial cells. This study provided novel insight into the mechanisms of DOX induced cardiotoxicity, and potential biomarkers or therapeutic targets were also proposed.