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Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown. To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan. In vitro experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the in vivo experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses. In vitro experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC50 = 10.6 μM) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant Ki was 0.574 μM and the binding constant αKi was 2.77 μM. In vivo experiments revealed that the AUC(0-T) (15.05 vs. 90.95 μg/mL·h) and AUC(0-∞) (15.05 vs. 91.99 μg/mL·h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT(0-∞) of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg·h after pretreatment with poziotinib. Poziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic. [ABSTRACT FROM AUTHOR]

Food–drug interactions are reported to have some impacts on the pharmacokinetics and pharmacodynamics of various oral drugs. To better understand the effects of naringenin, one natural product in many fruits, on the pharmacokinetics of rivaroxaban, drug–drug interactions (DDIs) between naringenin and rivaroxaban in vitro were investigated in Sprague–Dawley (SD) rat liver microsomes. For the DDIs in vivo, 12 male SD rats were randomly divided into the experimental group and the control group with six rats in each group. Rats in the experimental group were pre‐treated with naringenin (10 mg/kg/day) for 2 weeks before the administration of rivaroxaban (10 mg/kg) by oral gavage, while the rats in the control group were given rivaroxaban (10 mg/kg) only once. The plasma concentration of rivaroxaban in rats was then measured by UPLC‐MS/MS. In vitro data indicated that naringenin could decrease the metabolic clearance rate of rivaroxaban with the IC50 value of 38.89 μM, and exhibited a mixed inhibition to rivaroxaban (Ki =54.91 μM, aKi =73.33 μM, a = 0.74). In vivo data in rats revealed that as compared with that of the control group, the AUC(0–t) value of rats in the experimental group was increased from 2406.28 ± 519.69 μg/h/L to 4005.04 ± 1172.76 μg/h/L, the Cmax value was increased from 310.23 ± 85.76 μg/L to 508.71 ± 152.48 μg/L, and the Vz/F and CLz/F were decreased from 23.03 ± 4.81 L/kg to 16.2 ± 8.42 L/kg, 4.26 ± 0.91 L/h/kg to 2.57 ± 0.73 L/h/kg, respectively. These data indicated that naringenin had an inhibitory effect on the pharmacokinetics of rivaroxaban in rats, suggesting that the DDIs between naringenin and rivaroxaban might occur when they were co‐administered in the clinic. [ABSTRACT FROM AUTHOR]

A tandem Bischler–Napieralski/semipinacol rearrangement reaction has been developed for the purpose of assembling a bis(spirocyclic) indole framework, a privileged structural unit of aspidofractinine‐type monoterpenoid indole alkaloids, and was used in combination with a subsequent Mannich reaction to expeditiously construct the central bridged bicyclo[2.2.1]heptane ring system of these molecules with contiguous quaternary centers. The development of this novel strategy culminated in the collective total synthesis of four aspidofractinine alkaloids. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the pharmacokinetic effect of silibinin on methadone in rats. Twenty‐four male Sprague–Dawley rats were randomly divided into 4 groups: control group, single dose of 100 mg/kg group, multiple doses of 100 mg/kg group, and multiple doses of 30 mg/kg group. A single dose of 6 mg/kg methadone was administrated to rats orally without or with silibinin. Plasma samples were collected via tail vein at different time points and concentrations of methadone and its metabolite, 2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrrolidine (EDDP), were determined by ultra performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS). Compared with the control group (without silibinin), both 30 and 100 mg/kg silibinin significantly increased the Cmax of methadone, but only 100 mg/kg silibinin significantly increased the AUC(0‐t) of methadone and decreased its clearance. Pharmacokinetics parameters of EDDP were not altered by 30 mg/kg silibinin; its Tmax was decreased by 100 mg/kg silibinin and the Cmax was increased by single dose of 100 mg/kg silibinin. It is concluded that silibinin significantly altered the pharmacokinetics of methadone in rats by increasing the exposure of methadone. Further investigations in human should be conducted. Therapeutic drug monitoring of methadone in individuals undergoing methadone maintenance therapy is recommended when silibinin is concomitant. [ABSTRACT FROM AUTHOR]

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

Total syntheses of the biologically important and structurally unique tetracyclic diterpenes conidiogenone, conidiogenol, and conidiogenone B of the cyclopiane class are reported. The absolute configuration of naturally occurring conidiogenone B was also corrected. The key step of our strategy involved the highly efficient construction of both ring C and the quaternary carbon center shared by rings A and C through a one-step regioselective and diastereoselective cycloenlargement in the form of a semipinacol-type rearrangement. In particular, the desired regioselectivity was made possible by properly adjusting the migratory aptitude of the migrating carbon atom through the introduction of an electron-donating phenylthio group at this position. [ABSTRACT FROM AUTHOR]

1. CYP2C19 is a highly polymorphic enzyme responsible for the metabolism of a wide range of clinical drugs. Alterations to theCYP2C19gene contribute to the variability of CYP2C19 enzyme activity, which causes pharmacokinetics and drug efficacies to vary and adverse drug reactions to occur in different persons. Recently, we identified 24 novelCYP2C19allelic variants in the Chinese Han population. The purpose of present study is to assess the impact of these newly found nucleotide mutations on the enzymatic activity of the CYP2C19 protein. 2. Dual-expression vectors were constructed and transiently transfected into 293FT cells. Forty-eight hours after transfection, cells were re-suspended and incubated with two typical probe substrates, omeprazole andS-mephenytoin, to determine the activities of each variant relative to the wild-type protein. 3. Immunoblotting results showed that the protein expression levels of the CYP2C19 variants were diverse. Enzymatic ability analysis showed that the variant 35FS exhibited no functional activity, and most of the other variants showed significantly decreased metabolic activities toward both omeprazole andS-mephenytoin compared with wild-type. 4. These findings greatly enrich the knowledge of biological effects of these newly found CYP2C19 mutations and aid the application of this knowledge to future individualized drug therapy in clinic. [ABSTRACT FROM AUTHOR]

Aim: To determine the genetic basis of the low warfarin dose requirement in a Chinese patient. Materials & methods: Bi-directional sequencing of CYP2C9, VKORC1 and CYP4F2 genes was performed. CYP2C9 variants were highly expressed in yeast and insect-cell microsomes. Three typical CYP2C9 probe drugs were used to evaluate the catalytic activity. Results: A novel missense mutation (1400T>C) was identified in CYP2C9 and had been named as new allele *60. When expressed in yeast and insect cells, compared with wild-type enzyme, variant CYP2C9.60 exhibited lower protein expression capacity and showed significantly decreased metabolic activities for the hydroxylation of S-warfarin, tolbutamide and diclofenac. Conclusion: The novel mutation can greatly decrease the enzymatic activity of the CYP2C9 enzyme both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Background: Losartan and glimepiride are commonly used drugs to treat chronic diseases of hypertension and diabetes; they are both substrates of CYP2C9. The aim of the present study was to investigate the possible interaction of losartan and glimepiride both in vitro (rat liver microsomes) and in vivo (healthy Sprague-Dawley rats). Methods: In rat liver microsomes, 1-10 μmol/l losartan and glimepiride were coincubated, and the inhibitory effect was analyzed. In the subsequent pharmacokinetic study, 15 healthy Sprague-Dawley rats received administrations of 5 mg/kg losartan or 1 mg/kg glimepiride or a coadministration. Results: In the rat liver microsome system, glimepiride showed a slight inhibition of losartan at concentrations of 1-10 μmol/l, whereas losartan exhibited no inhibitory effect on glimepiride. In vivo, glimepiride did not modify the plasma concentration of losartan and its metabolite E-3174. The alteration of an increased AUC and Cmax was observed in the pharmacokinetic parameters of glimepiride and hydroxy glimepiride. Conclusions: Glimepiride did not affect losartan pharmacokinetics in rats, while losartan potently altered glimepiride metabolism; this result was inconsistent with the in vitro outcome. The mechanism requires further investigation. In clinical settings, attention should be paid to the interaction of these two drugs in the human body as well as the possible adverse reactions of glimepiride. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Of the 57 reported CYP2 C9 alleles, to date, 36 of them have been identified in the Chinese population. The aim of this study was to assess the catalytic characteristics of these allelic isoforms and their effects on the metabolism of glimepiride in vitro. Baculovirus-mediated expressing system was used to highly express wild-type and the 35 CYP2 C9 allelic variants in insect cell microsomes. Then, the enzymatic characteristics of each variant were evaluated using glimepiride as the substrate. Reactions were performed at 37°C with the insect microsomes and 0.125-10 μM glimepiride for 40 min. After termination, the products were extracted and used for signal collection by LC- MS/ MS. Of the 36 tested CYP2 C9 allelic isoforms, only four variants ( CYP2 C9.40, CYP2 C9.47, CYP2 C9.51 and CYP2 C9.54) exhibited similar relative clearance values to that of wild-type CYP2 C9.1. In addition, one variant ( CYP2 C9.36) showed a higher intrinsic clearance value than the wild-type protein, while the remaining 30 CYP2 C9 allelic isoforms exhibited significantly decreased clearance values (from 0.1% to 87.2%) compared to CYP2 C9.1. This study provided the most comprehensive data on the enzymatic activities of all reported CYP2 C9 variants in the Chinese population with regard to the commonly used antidiabetic drug, glimepiride. Our results indicate that most of the tested rare alleles significantly decrease the catalytic activity of CYP2 C9 variants towards glimepiride hydroxylation in vitro. [ABSTRACT FROM AUTHOR]

1. CYP2C9 is an important member of the cytochrome P450 enzyme superfamily, with 57 CYP2C9 allelic variants being previously reported. Among these variants, we recently identified 21 novel alleles ( *36-*56) in the Han Chinese population. The aim of this study was to assess the catalytic activities of 36 CYP2C9 variants found in the Chinese population toward losartan in vitro. 2. Insect microsomes expressing the 36 CYP2C9 variants were incubated with 0.5-25 μM losartan for 30 min at 37 °C. Next, the products were extracted, and signal detection was performed using high-performance liquid chromatography. 3. Compared with wild-type CYP2C9.1, the intrinsic clearance ( Vmax /Km) values of all variants except for CYP2C9.56 were significantly altered. One variant exhibited markedly increased values (>250%), whereas 33 variants exhibited significantly decreased values (from 20 to 96%) due to increased Km and/or decreased Vmax values. 4. These findings suggest that more attention should be paid to subjects carrying these infrequent CYP2C9 alleles when administering losartan in the clinic. [ABSTRACT FROM AUTHOR]

Aim:Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme that is responsible for the metabolism of approximately 15% of clinically important drugs. The aim of this study was to assess the catalytic characteristics of 37 CYP2C9 allelic isoforms found in Chinese Han population on the metabolism of tolbutamide in vitro.Methods:The wild-type and 36 CYP2C9 variants were expressed in sf21 insect cells using a baculovirus-mediated expression system. Then the insect microsomes were prepared for assessing the metabolic characteristics of each variant toward the CYP2C9-specific drug substrate tolbutamide.Results:Of 36 allelic variants tested, the intrinsic clearance values of 2 allelic isoforms (CYP2C9.36 and CYP2C9.51) were much higher than the wild-type CYP2C9.1 protein, 3 allelic isoforms (CYP2C9.11, CYP2C9.56 and N418T) exhibited similar intrinsic clearance values as the wild-type enzyme, whereas the other 31 variants showed significantly reduced intrinsic clearance values, ranging from 0.08% to 66.88%, for tolbutamide.Conclusion:Our study provides the most comprehensive data concerning the enzymatic activity of the CYP2C9 variants that are present in the Chinese Han population, and our data suggest that most of the carriers of these alleles might be paid more attention when using CYP2C9 mediated drugs clinically. [ABSTRACT FROM AUTHOR]

A new arbitrary Lagrangian-Eulerian method, global ALE method (GALE), is developed for compressible multimaterial flows with large deformation of interface. Unlike traditional ALE methods, where rezoning and remapping are performed only in the internal of one material region, and material interfaces are tracked by Lagrangian mesh lines, the GALE method attempts a compromise by combining the merits of both ALE and Eulerian methods by global remeshing and remapping. In the GALE method, modern Eulerian methods, such as mass fraction model, level set method, are coupled with a Godunov-type ALE method. Some benchmark problems, such as gas-liquid shock tube problem and stratified Richtmyer-Meshkov instability, were computed by the GALE to verify the method, and the numerical results agree well with exact solution or theoretical model. [ABSTRACT FROM AUTHOR]

The article presents a chemical reaction for the synthesis of natural products such as tetracyclic cyclopiane diterpenes conidiogenone, conidiogenol, and conidiogenone B.

Warfarin is the most commonly used anticoagulant in the clinical treatment of thromboembolic diseases. The dose of warfarin varies significantly within populations, and the dose is closely related to the genetic polymorphisms of the CYP2C9 and VKORC1 genes. In this study, a new CYP2C9 nonsynonymous mutation (8576C > T) was detected after the genetic screening of 162 patients took warfarin. This mutation, named as the new allele CYP2C9*62 , can result in an arginine to cysteine amino acid substitution at position 125 of the CYP2C9 protein (R125C). When expressed in insect cells, the protein expression of CYP2C9.62 was significantly lower than that of the wild-type, and its metabolic activity was also significantly decreased after the addition of three typical CYP2C9 probe drugs, suggesting that the new mutant can dramatically affect the metabolism of CYP2C9 drugs in vitro. [ABSTRACT FROM AUTHOR]