Main Pharmacokinetic Parameters Research Articles

Bioequivalence Study of 2 Formulations of Fluticasone Nasal Spray in Healthy Chinese Volunteers.

This study aimed to evaluate the pharmacokinetic characteristics, safety, and bioequivalence of 2 formulations of fluticasone nasal spray in healthy Chinese subjects. A single-center, randomized, open-label, single-dose, 2-formulation, 2-sequence, 2-period crossover bioequivalence study was conducted under fasting conditions. A total of 120 healthy male and female subjects were enrolled, of which 119 subjects completed the entire study. The main pharmacokinetic parameters of the parent drug, fluticasone propionate (FP), in plasma were as follows: For the test formulation, maximum plasma concentration (Cmax) was 10.3pg/mL, area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC0-t) was 65.6pg•h/mL, and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) was 86.4pg•h/mL. For the reference formulation: Cmax was 8.80pg/mL, AUC0-t was 58.2pg•h/mL, and AUC0-∞ was 75.2pg•h/mL. The 90% confidence intervals of the geometric means for AUC0-t, AUC0-∞, and Cmax between the 2 formulations were 105%-120%, 103%-120%, and 112%-124%, respectively. The results show that the test and reference formulations were well tolerated, with no serious adverse events reported. According to the criteria for bioequivalence, the FP nasal spray (test formulation) is bioequivalent to the reference formulation.

Pharmacokinetic validation of a new protocol of chronic oral administration of aripiprazole in male C57 Bl/6 mice through drinking solution.

Schizophrenia is a chronic mental illness, with a prevalence of about 1%. The symptoms are classified in three categories: positive symptoms, negative symptoms and deficits in cognitive function. Regarding the pharmacological treatment, current antipsychotics mainly improve positive symptoms while negative and cognitive symptoms remain inadequately treated. Among them, aripiprazole, through its pharmacological properties results in regulation of positive symptoms and, to a lesser extent, to negative and cognitive ones. Drug treatment studies in animals typically employ administration methods such as injection or gavage, which is time-consuming over long periods, does not reflect route of administration used in patients, and cause substantial stress in animals. We assessed herein the pharmacokinetic properties and behavioural effects of aripiprazole after chronic administration via drinking solution in C57Bl/6 mice. Results show that subchronic administration of 1 and 10 mg/kg doses of aripiprazole via drinking solution present significant blood concentrations, without any significant effect on the spontaneous activity of mice (between 10 am and 3 pm). Furthermore, we described for the first time to our knowledge the main pharmacokinetic parameters of aripiprazole after gavage acute administration (10 mg/kg). Collectively, all of these data will be very useful in future projects including chronic administrations (several months) of this antipsychotic.

Development of a UPLC-MS/MS method for the determination of sulfatinib and its no interaction with myricetin in rats.

Sulfatinib is a novel oral tyrosine kinase inhibitor (TKI) with selective inhibition of fibroblast growth factor (FGFR), colony-stimulating factor 1 receptor (CSF-1R) and vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. It has been approved for the therapy of neuroendocrine tumors arising in the non-pancreatic (December 2020) and pancreatic (June 2021) glands. Until now, there has no research on the determination of sulfatinib in biological medium by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The current study validated a sensitive and reliable quantitative detection of sulfatinib in plasma using UPLC-MS/MS for the first time, and investigated the interaction with myricetin in rats. Acetonitrile was used to precipitate the plasma protein, and lenvatinib was employed as the internal standard (IS). The method demonstrated that sulfatinib presented high linearity over the concentration of 11-2,000ng/mL with the lower limit of quantification (LLOQ) of 1ng/mL. It was validated methodologically that the precision, matrix effect, stability, accuracy and extraction recovery were all within the allowable values. Moreover, male Sprague-Dawley (SD) rats were assigned randomly to assess the interaction between sulfatinib (30mg/kg) and myricetin (50mg/kg). Nevertheless, no significant differences of the main pharmacokinetic parameters were revealed. This may be due to insufficient doses of myricetin, or failure of myricetin to act in a timely manner in vivo. The findings contributed to a better understanding of the metabolism and drug-drug interaction of sulfatinib, but the presence or absence of interactions needs to be confirmed by further studies.

Evaluating the drug-drug interactions of SHR4640 on repaglinide and midazolam in healthy subjects

ABSTRACT Background SHR4640, a highly selective URAT1 inhibitor, was evaluated to investigate its inhibitory effects on CYP2C8 and CYP3A4 in vivo clinical trial. This study assessed the pharmacokinetic (PK) impact of SHR4640 when co-administered with the CYP2C8 probe substrate repaglinide and the CYP3A4 probe substrate midazolam. Research design and methods In this single-center, randomized, double-blind, placebo-controlled study, participants were randomly allocated in a 1:1:1 ratio to SHR4640 Group A, SHR4640 Group B, and placebo group and received oral repaglinide, midazolam, SHR4640 or placebo at specific times. The primary endpoints included the main PK parameters of repaglinide and midazolam, both alone and in combination with SHR4640 (AUC0-inf, AUC0-t, and Cmax). Results The increase in the area under the concentration-time curve (AUC) for repaglinide, when co-administered with SHR4640, was less than 1.25-fold, while the AUC for midazolam exhibited a slight increase of 46%. Conclusions SHR4640 exerts a weak inhibitory effect on the AUC of CYP enzyme probe substrates and has minimal potential for drug-drug interactions and presents a favorable safety profile. Clinical trial registration www.clinicaltrials.gov identifier is NCT06196580 (Name: PK Effects of SHR4640 on Repaglinide and Midazolam, and the Impact of SHR4640 on QT Interval).

A Phase I Clinical Trial to Evaluate the Bioequivalence of an Adalimumab Biosimilar Adalimumab-WIBP and Humira®.

The high costs associated with biological agents often limit accessibility for many patients, whereas biosimilars allow the wider application of biological treatment. The objectives of this phase I clinical trial were to compare the pharmacokinetics, immunogenicity, and safety profiles of the biosimilar adalimumab-WIBP and the reference product Humira® and to assess the precision of the bioequivalence evaluation. In this randomized, double-blind, parallel-group bioequivalence study, 164 healthy male Chinese participants were selected and randomly divided into two groups on a 1:1 ratio. The subjects were administered a single 40 mg subcutaneous dose of either adalimumab-WIBP or Humira®. Blood samples extracted at multiple intervals after administration were analyzed to interpret pharmacokinetic parameters, and any adverse events were documented. Alongside ensuring safety measures, the subjects were monitored for immunogenicity. The pharmacokinetic results demonstrated similar serum concentration-time curves in both groups. There were no significant differences in safety and no differences in immunogenicity profiles between the two groups. The bioequivalence was confirmed: the 90% confidence interval for the geometric mean ratio of the main pharmacokinetic parameters was within the range of 80-125%. The trial indicated the bioequivalence between adalimumab-WIBP and the reference product Humira® based on pharmacokinetics, immunogenicity, and safety profile. These findings reinforce the use of the adalimumab-WIBP biosimilar as a possible therapeutic alternative to Humira®.

Pharmacokinetic study of a new 4,5-dihydroisoxazole-5-carboxamide derivative in rats

Introduction. 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-N-[4-methoxy-3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxamide (R004) is a prospective new molecule for the treatment of rheumatoid arthritis. This compound is at the stage of preclinical research, during which its pharmacokinetics must be studied along with efficacy and safety. In this case, it is necessary to establish the main pharmacokinetic parameters of the drug and its metabolites in blood plasma after a single administration.Aim. Evaluation of linearity of pharmacokinetics and relative bioavailability of 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-N-[4-methoxy-3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxamide and its main metabolites in plasma after a single administration of the substance to rats.Materials and methods. Substance R004 was administered to rats once orally at dosages of 10 mg/kg, 20 mg/kg and 40 mg/kg and intraperitoneally at a dosage of 10 mg/kg. The study was carried out using 24 Wistar rats: 6 rats were used for each of the dosage. Blood samples were collected before administration and 30 min, 1 h, 1 h, 30 min, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h after administration of the drug. The obtained plasma was stabilized with a 250 mM ammonium acetate solution to prevent hydrolysis of R004. Plasma samples were prepared by means proteins precipitation by acetonitrile solution of internal standards. Measurement of the concentration of R004 and its metabolites 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid (M1) and 4-methoxy-3-(trifluoromethyl)aniline (M2) was performed using HPLC-MS/MS. A non-compartment approach was applied for evaluation pharmacokinetic parameters.Results and discussion. The developed bioanalytical method has been fully validated in accordance with the requirements of the EAEU guideline for conducting bioequivalence study and ICH M10 guideline. The analytical range of determination in plasma of R004 was 2–2000 ng/ml, M1 and M2 – 1–1000 ng/ml. The dependence of the parameters Cmax and AUC0–t of the studied compound and its metabolites on the administered dose was linear. Thus, the value of the correlation coefficient of Cmax R004 was 0.9995, and value of the correlation coefficient of AUC0–t was 0.9991. The presence of enterohepatic recirculation R004 has been determined. The relative bioavailability of R004 was 21.26%.Conclusion. The developed method was successfully applied for the pharmacokinetic research. R004 and its metabolites have linear pharmacokinetics in case of oral administration.

A Study of the Comparability of the Pharmacodynamic, Toxicological, and Pharmacokinetic Properties of the Reference Drug Pulmozyme® and the Biosimilar Drug Tigerase®.

The article presents the results of studies of the drug Tigerase® (inhalation solution manufactured by JSC GENERIUM, Russia), conducted to obtain evidence of its similarity (comparability) to the reference drug Pulmozyme® (inhalation solution, manufactured by Hoffmann-La Roche Ltd., Switzerland). Both drugs contain human recombinant deoxyribonuclease I (dornase alfa) as an active substance and are intended for the treatment of cystic fibrosis with pulmonary manifestations (mucoviscidosis). The enzymatic activity of dornase alfa, contained in the studied drugs, was investigated in vitro and ex vivo on samples of purulent sputum of patients. The pharmacokinetic parameters of the drugs in the blood serum, bronchi, and lungs, as well as the main physiological parameters (body weight and temperature, the state of the cardiovascular, respiratory, excretory systems, hematological and biochemical blood parameters, pathomorphological changes in internal organs (including the state of the cornea), and mortality rates) were investigated in comparative studies of subchronic toxicity in juvenile and mature rats with 28-day inhalation at doses of 0.2 mg/kg for mature animals and 0.26 mg/kg for juvenile animals (the dose was 6 times higher than the dose recommended for clinical use). The results of the studies allow us to conclude that the drugs are comparable in enzymatic, mucolytic (secretolytic) DNase activity, safety profile and main pharmacokinetic parameters.

Pharmacometabolomics Approach to Explore Pharmacokinetic Variation and Clinical Characteristics of a Single Dose of Desvenlafaxine in Healthy Volunteers.

This study investigated the effects of a single dose of desvenlafaxine via oral administration on the pharmacokinetic parameters and clinical and laboratory characteristics in healthy volunteers using a pharmacometabolomics approach. In order to optimize desvenlafaxine's therapeutic use and minimize potential adverse effects, this knowledge is essential. Methods: Thirty-five healthy volunteers were enrolled after a health trial and received a single dose of desvenlafaxine (Pristiq®, 100 mg). First, liquid chromatography coupled to tandem mass spectrometry was used to determine the main pharmacokinetic parameters. Next, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used to identify plasma metabolites with different relative abundances in the metabolome at pre-dose and when the desvenlafaxine peak plasma concentration was reached (pre-dose vs. post-dose). Results: Correlations were observed between metabolomic profiles, such as tyrosine, sphingosine 1-phosphate, and pharmacokinetic parameters, as well as acetoacetic acid and uridine diphosphate glucose associated with clinical characteristics. Our findings suggest that desvenlafaxine may have a broader effect than previously thought by acting on the proteins responsible for the transport of various molecules at the cellular level, such as the solute carrier SLC and adenosine triphosphate synthase binding cassette ABC transporters. Both of these molecules have been associated with PK parameters and adverse events in our study. Conclusions: This altered transporter activity may be related to the reported side effects of desvenlafaxine, such as changes in blood pressure and liver function. This finding may be part of the explanation as to why people respond differently to the drug.

Determination of QLNC-3A6 in canine plasma by UHPLC-MS/MS and its application in pharmacokinetic studies

Multi-targeted tyrosine kinase inhibitor QLNC-3A6 Di-maleate, a structurally novel small molecule compound, has therapeutic efficacy for the treatment of canine cutaneous mast cell tumor (CMCT) caused by mutations in the c-Kit gene. Since pharmacokinetic (PK) information plays an important role in the development and application of new drugs, etc., a rapid, highly sensitive and selective UHPLC-MS/MS analytical method was developed and validated for the first time in this study for the quantitative detection of QLNC-3A6 in canine plasma. 100 µL of plasma was precipitated using 350 µL of acetonitrile, and Chromatographic separation was performed on a Phenomenex Kinetex C18 column (50 × 2.1 mm, 2.6 µm) at a flow rate of 0.4 mL/min, the mobile phases were set to 0.1% formic acid aqueous solution (A) and 0.1% formic acid acetonitrile (B). The calibration curve linear range was 0.5–100 ng/mL (R 2>0.99). The intraday and interday precision values (relative standard deviation, RSD) were 2.06–13.57% and 6.90–9.14%. Intraday and interday accuracies were −10.73 to 9.54% and −3.86 to 0.70% respectively. The dilution integrity RSD value and stability RSD value were less than 3.77 and 7.45%, respectively. Subsequently, the pharmacokinetics were investigated in canine after oral administration of QLNC-3A6 Di-maleate tablets at a dose of 3 mg/kg BW using this method. The results showed that QLNC-3A6 showed fast absorption rate, rapid distribution and slow metabolic elimination in canine plasma. The results of the main PK parameters including λz, T 1/2λz, C max, T max and AUC last were 0.07 ± 0.01/h, 11.00 ± 2.57 h, 50.88 ± 31.94 ng/mL, 9.08 ± 11.57 h and 836.48 ± 230.53 ng h/mL, respectively.

Magnetically targeted lidocaine sustained-release microspheres: optimization, pharmacokinetics, and pharmacodynamic radius of effect

ObjectiveThis study aimed to optimize the formulation of magnetically targeted lidocaine microspheres, reduce the microsphere particle size, and increase the drug loading and encapsulation rate of lidocaine. The optimized microspheres...

Воспроизведенная комбинация модуляторов белка CFTR — ивакафтора и лумакафтора. Этические и фармакокинетические аспекты

The lack of effective and affordable therapies for rare diseases is an important ethical issue. One example is cystic fibrosis (CF), a chronic, progressive disease characterized by an impaired function of all exocrine glands. The combination of ivacaftor and lumacaftor (CFTR potentiator and corrector) should lead to a sufficient level of protein on the cell surface and to an increase in its activity, thereby correcting the impaired function. Development of a generic drug containing ivacaftor and lumacaftor as active pharmaceutical substances will increase the availability of this medication and improve patient survival. To study comparative pharmacokinetics and bioequivalence of drugs containing ivacaftor and lumacaftor in healthy volunteers. It was conducted as an open-label, randomized, crossover bioequivalence study involving a single intake of the drug during each period under fed condition in healthy male and female volunteers. The conclusion about bioequivalence was made if 90% confidence interval for primary pharmacokinetic parameters (Cmax, AUC0-t) fell within the accepted bioequivalence limits of 80–125%. According to the results of the study, it was shown that the values of 90% CI of the geometric mean of the main pharmacokinetic parameters for ivacaftor and lumacaftor fall within the acceptance limits for bioequivalence. According to the applied criteria, the drugs are bioequivalent, which makes it possible to recommend the investigational drug to the Ministry of Health of the Russian Federation for obtaining the registration status.

Relative bioavailability, immunogenicity, and safety of two adalimumab-adbm formulations in healthy volunteers: a double-blind, randomized, single-dose, parallel-arm Phase I trial (VOLTAIRE-HCLF)

ABSTRACT Objective VOLTAIRE-HCLF compared the relative bioavailability of citrate-free high-concentration and reference formulations of the biosimilar adalimumab-adbm (Cyltezo®), including pharmacokinetic (PK) profiles, immunogenicity, and safety profiles in healthy volunteers. Methods Healthy volunteers (N = 200) aged 18–55 years and with body mass index of 18.5–29.9 kg/m2 and no prior exposure to adalimumab were randomized in a 1:1 ratio to receive a single subcutaneous injection of either adalimumab-adbm 40 mg/0.4 mL (high-concentration formulation) or 40 mg/0.8 mL (reference formulation). Participants completed 13 follow-up visits over 57 days, followed by a safety follow-up period of up to 70 days. Results The main PK parameters were similar for the high-concentration and reference groups. For all primary endpoints, the geometric mean ratios and 90% confidence intervals of AUC0–1344, AUC0–∞, and Cmax for both groups were entirely within the standard 80–125% bioequivalence acceptance range at 101.88% (93.31–111.23%), 105.38% (95.06–116.81%), and 91.29% (84.38–98.76%), respectively. There were no differences in the proportion of anti-drug antibody-positive participants or in the distribution of anti-drug antibody titers between the two formulations at any time point after drug dosing. Participants who were given the high-concentration formulation of adalimumab-adbm experienced a lower incidence of adverse events and local reactions than those who were given the reference formulation. Conclusions Overall, the high-concentration and reference adalimumab-adbm formulations had highly similar PK and immunogenicity profiles and were safe and well tolerated. Clinical trial registration NCT05203289

Research Note: Pharmacokinetics of bromhexine hydrochloride in broilers after single oral and intravenous administration

The current study aimed to investigate the pharmacokinetics of bromhexine hydrochloride in broilers after single intravenous (IV) and oral (PO) administration at 2.5 mg/kg body weight (BW). The trial adopted a randomized, parallel-controlled design, where 20 twelve-wk-old broilers were randomly assigned to either the PO or IV group. Blood samples were collected at predetermined time points, and plasma was further separated for analysis. The bromhexine hydrochloride concentrations in plasma samples were determined using an ultra-performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method. Noncompartmental analysis (NCA) using Phoenix software was conducted to analyze the concentration versus time data of bromhexine hydrochloride in every chicken. Subsequently, the main pharmacokinetic parameters between the 2 groups were statistically analyzed using SPSS software. Results from NCA revealed that after oral administration at 2.5 mg/kg BW, bromhexine hydrochloride exhibited slow absorption, reaching an average peak concentration of 32.72 ng/mL at 1.78 h. However, incomplete absorption was observed, with an absolute bioavailability of only 20.06% ± 10.84%. Additionally, bromhexine hydrochloride displayed wide distribution, with a steady-state distribution volume (VSS) of 22.55 ± 13.45 L/kg, and slow elimination, with a clearance (Cl) of 1.52 ± 0.38 L/h/kg. Furthermore, gender effects were assessed on the pharmacokinetics of bromhexine hydrochloride in broilers, revealing better absorption in male broilers compared to females. This disparity may be attributed to the faster blood flow and richer blood volume typically found in male broilers.

Study on genotype and phenotype of novel CYP2D6 variants using pharmacokinetic and pharmacodynamic models with metoprolol as a substrate drug.

To investigate the pharmacokinetic and pharmacodynamic profiles of volunteers carrying CYP2D6 genotypes with unknow metabolic phenotypes, a total of 22 volunteers were recruited based on the sequencing results. Peripheral blood and urine samples were collected at specific time points after oral administration of metoprolol. A validated high-performance liquid chromatography (HPLC) method was used to determine the concentrations of metoprolol and α-hydroxymetoprolol. Blood pressure and electrocardiogram were also monitored. The results showed that the main pharmacokinetic parameters of metoprolol in CYP2D6*1/*34 carriers are similar to those in CYP2D6*1/*1 carriers. However, in individuals carrying the CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 genotypes, the area under the curve (AUC) and half-life (t1/2) of metoprolol increased by 2-3 times compared to wild type. The urinary metabolic ratio of metoprolol in these genotypes is consistent with the trends observed in plasma samples. Therefore, CYP2D6*1/*34 can be considered as normal metabolizers, while CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 are intermediate metabolizers. Although the blood concentration of metoprolol has been found to correlate with CYP2D6 genotype, its blood pressure-lowering effect reaches maximum effectiveness at a reduction of 25 mmHg. Furthermore, P-Q interval prolongation and heart rate reduction are not positively correlated with metoprolol blood exposure. Based on the pharmacokinetic-pharmacodynamic model, this study clarified the properties of metoprolol in subjects with novel CYP2D6 genotypes and provided important fundamental data for the translational medicine of this substrate drug.

Bioavailability Study of Experimental Push–pull Osmotic Pump Tablet of Nifedipine in Dogs

This study aimed to assess the bioavailability of experimental extended-release nifedipine tablets of push-pull osmotic pump type composed of a semipermeable membrane-coated bilayer core tablet containing PEO N10 and PEO 303 in drug layer and push layer, respectively on dogs. A test on dogs was performed using a two-way randomized crossover design with a single oral dose, fasting condition. Plasma samples were obtained at intervals and analyzed for nifedipine by UPLC-MS/MS after liquid-liquid extraction using glibenclamide as the internal standard. The pharmacokinetic parameters were calculated and the bioavailability of nifedipine extended-release tablets was evaluated by comparing the pharmacokinetic parameters between the prepared extended-release tablets of 30 mg NIF and the reference tablets of Adalat LA 30 mg. It was found that the prepared push-pull osmotic pump tablets of 30 mg nifedipine were equivalent in bioavailability to Adalat LA reference tablets of 30 mg nifedipine in experimental dogs according to the regulations of US-FDA and Vietnamese pharmacopeia 5th edition. The main pharmacokinetic parameters of nifedipine test and reference tablets after a single oral administration were as follows: Cmax 26.95 ± 7.82 (ng.mL-1) and 27.20 ± 6.99 (ng.mL-1), Tmax 12.33 ± 3.44 hours and 11.50 ± 3.33 hours, AUC0-96 728.96 ± 328.87 (ng.h.mL-1) and 702.48 ± 404.48 (ng.h.mL-1), AUC0-∞, 741.05 ± 340.39 (ng.h.mL-1) and 710.71 ± 408.76 (ng.h.mL-1), MRT 21.80 ± 5.25 hours and 22.06 ± 5.20 hours, respectively. The 90% confidence intervals for the ratio of Cmax, AUC0-∞, and MRT values for the test and reference products, using logarithmically transformed data were 90.82% - 108.09%, 91.97% - 118.21%, 90.74% -107.62%, respectively. No statistically significant difference was found for the Tmax value.

The place of berberine in the treatment of metabolic syndrome

The article highlights the pharmacological activity of berberine, as well as its place in the treatment of the current epidemic - metabolic syndrome. The review examines the molecular mechanisms that allows achieving anti-inflammatory, antimicrobial and antioxidant effects in detail. Berberine’s pharmacological profile makes it possible to have a positive effect on the pathway of obesity, non-alcoholic fatty liver disease, dyslipoproteinemia, the intestinal microbiome and insulin resistance. In addition, the article reviews the main pharmacokinetic parameters and side effects of chemically unmodified berberine.

Simultaneous determination of iguratimod and its metabolite in rat plasma using a UPLC-MS/MS method: Application for drug-drug interaction

This aim of the work was to establish an acceptable sensitive assay based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for quantitatively analyzing the plasma concentrations of iguratimod (IGR) and its metabolite M2 in rats, and to further investigate the effect of fluconazole on the pharmacokinetics of IGR and M2. The mobile phase consisted of acetonitrile and water with 0.1% formic acid, was used to separate IGR, M2 and internal standard (IS) fedratinib on a UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) with the flow rate of 0.4 mL/min. Positive ion mode and multiple reaction monitoring (MRM) were used to construct the quantitative analysis. The calibration standard of IGR and M2 covered 2–10000 and 1–1000 ng/mL respectively, with the lower limit of quantification (LLOQ) as 2 ng/mL and 1 ng/mL respectively. In addition, selectivity, recovery, accuracy, precision, matrix effect and stability of the method validation program were well accepted in this work. Subsequently, this approach was used to assess the effect of fluconazole on the pharmacokinetics of IGR and M2 in rats. In the presence of 20 mg/kg fluconazole (experimental group), we found the main pharmacokinetic parameters were significantly altered when compared with 2.5 mg/kg IGR alone (control group). Among them, AUC(0-∞) and Cmax of IGR in the experimental group was 1.43 and 1.08 times higher than that of the control group, respectively. Moreover, we also found that the other main pharmacokinetic parameters of M2 had no significant changes, except t1/2z and Tmax. In conclusion, fluconazole significantly altered the main pharmacokinetics of IGR and M2 in rats. It implys that we should pay more attention to the adverse reaction of IGR when the concomitant use of fluconazole and IGR occur in the future clinical practice.

Bioequivalence Study of Tebipenem Pivoxil in Healthy Chinese Adults.

Tebipenem pivoxil (TP) is a carbapenem and is applied against pneumonia, otitis media, and sinusitis. This study compared the pharmacokinetics (PK) and safety of a test (T) preparation and reference (R) preparation of TP in healthy Chinese adults. This study was a single-center, randomized, open, single-dose (fasting/postprandial) oral administration, two-agent, two-sequence, two-cycle, crossover bioequivalence trial. A total of 60 participants were enrolled (24 fasting and 36 postprandial). All participants were randomly assigned to the TR sequence and RT sequence. Subsequently, they switched T sequences or R sequences 7 days later. PK blood samples were collected according to the protocol, plasma TP concentration was determined by liquid chromatography-mass spectrometry, main PK parameters were calculated based on a non-compartment model, and adverse events were recorded during the test. In the feeding arm, the geometric mean ratio of maximum concentration (Cmax) was 89.84% (90% confidence interval 84.33-95.70), the geometric mean ratio of area under the plasma concentration-time curve from time 0 to last time of quantifiable concentration (AUC0-t) was 86.80% (83.62-90.10), and the geometric mean ratio of area under the plasma concentration-time curve from time 0 to infinity time of quantifiable concentration (AUC0-∞) was 86.90% (83.73-90.20), which were within the acceptable range of bioequivalence (80-125%). In the fasting arm, the geometric mean ratio of Cmax was 96.07% (89.62-102.99), the geometric mean ratio of AUC0-t was 93.09% (90.47-95.78), and the geometric mean ratio of AUC0-∞ was 93.09% (90.48-95.77), which was within the acceptable range of bioequivalence (80-125%). Hence, the T preparation and R preparation of TP had bioequivalence in the fasting arm and feeding arm of the clinical trial. In addition, all adverse events were mild, and no severe adverse events were noted. Preparations T and R of TP were bioequivalent in the fasting and postprandial groups in clinical trials, and TP was safe.

Effects of myricetin and quercetin on ticagrelor metabolism and the underlying mechanism

The aim of this study was to investigate the potential drug-drug interactions (DDIs) between ticagrelor and other drugs as well as their underlying mechanisms. Rat liver microsome (RLM) reaction system was used to screen potential DDIs in vitro, and ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was applied to detect the levels of ticagrelor and AR-C124910XX, the main metabolite of ticagrelor. A total of 68 drugs were screened, 11 of which inhibited the production of AR-C124910XX to 20% or less, especially two flavonoids (myricetin and quercetin). The half-maximal inhibitory concentration (IC50) of myricetin on ticagrelor was 11.51 ± 0.28 μM in RLM and 17.96 ± 0.54 μM in human liver microsome (HLM). The IC50 of quercetin in inhibiting ticagrelor in RLM and HLM was 16.92 ± 0.49 μM and 60.15 ± 0.43 μM, respectively. They all inhibited the metabolism of ticagrelor through a mixed mechanism. In addition, Sprague-Dawley (SD) rats were used to study the interactions of ticagrelor with selected drugs in vivo. We found that the main pharmacokinetic parameters including AUC (0-t), AUC (0-∞) and Cmax of ticagrelor were significantly increased when ticagrelor was combined with these two flavonoids. Our results suggested that myricetin and quercetin of flavonoids both had significant effects on the metabolism of ticagrelor, providing reference data for the clinical individualized medication of ticagrelor.

Effects of vitamin C on the pharmacokinetics and pharmacodynamics of nimodipine in rats.

In recent years, researchers have shown a growing interest in the interactions between different pharmaceutical agents. An intriguing instance lies in the possible interaction between nimodipine and vitamin C. To investigate the pharmacokinetic and pharmacodynamic effects of vitamin C on nimodipine in rats, rats were randomly divided into a nimodipine only group and a combination group (nimodipine + vitamin C). The two groups were given intragastric administration and nimodipine blood concentrations were determined using high-performance liquid chromatography-tandem mass spectrum at different time points. Blood pressure and heart rate were measured via carotid artery cannulation. Pharmacokinetic differences were observed between the nimodipine only group and the combination group at the same dose. Compared with the nimodipine only group, the combination group's main pharmacokinetic parameters of peak concentration and area under the curve increased significantly, and the difference was statistically significant (p < 0.05); furthermore, the combination group exhibited a significant reduction in average blood pressure, while no significant effects on heart rate were observed. Vitamin C did not affect the activity of CYP450 in rat liver. The pharmacokinetic characteristics and pharmacodynamics of nimodipine were changed by vitamin C administration in rats.