scholarly journals Efficacy, metabolism and pharmacokinetics of Ro 15-5458, a forgotten schistosomicidal 9-acridanone hydrazone

2020 ◽  
Vol 75 (10) ◽  
pp. 2925-2932
Author(s):  
Alexandra Probst ◽  
Cécile Häberli ◽  
Dionicio Siegel ◽  
Jianbo Huang ◽  
Seth Vigneron ◽  
...  
Keyword(s):  
Oral Dose ◽  
High Activity ◽  
Liver Microsomes ◽  
Human Hepatocytes ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Drug Induced ◽  
Stage Specificity ◽  
Human And Mouse

Abstract Background Treatment of schistosomiasis, a neglected disease, relies on just one partially effective drug, praziquantel. We revisited the 9-acridanone hydrazone, Ro 15-5458, a largely forgotten antischistosomal lead compound. Methods Ro 15-5458 was evaluated in juvenile and adult Schistosoma mansoni-infected mice. We studied dose–response, hepatic shift and stage specificity. The metabolic stability of Ro 15-5458 was measured in the presence of human and mouse liver microsomes, and human hepatocytes; the latter also served to identify metabolites. Pharmacokinetic parameters were measured in naive mice. The efficacy of Ro 15-5458 was also assessed in S. haematobium-infected hamsters and S. japonicum-infected mice. Results Ro 15-5458 had single-dose ED50 values of 15 and 5.3 mg/kg in mice harbouring juvenile and adult S. mansoni infections, respectively. An ED50 value of 17 mg/kg was measured in S. haematobium-infected hamsters; however, the compound was inactive at up to 100 mg/kg in S. japonicum-infected mice. The drug-induced hepatic shift occurred between 48 and 66 h post treatment. A single oral dose of 50 mg/kg of Ro 15-5458 had high activity against all tested S. mansoni stages (1-, 7-, 14-, 21- and 49-day-old). In vitro, human hepatocytes produced N-desethyl and glucuronide metabolites; otherwise Ro 15-5458 was metabolically stable in the presence of microsomes or whole hepatocytes. The maximum plasma concentration was approximately 8.13 μg/mL 3 h after a 50 mg/kg oral dose and the half-life was approximately 4.9 h. Conclusions Ro 15-5458 has high activity against S. mansoni and S. haematobium, yet lacks activity against S. japonicum, which is striking. This will require further investigation, as a broad-spectrum antischistosomal drug is desirable.

scholarly journals Metabolism and Pharmacokinetic Study of the Boron-Containing Prodrug of Belinostat (ZL277), a Pan HDAC Inhibitor with Enhanced Bioavailability

2019 ◽  
Vol 12 (4) ◽  
pp. 180 ◽  
Author(s):  
Changde Zhang ◽  
Shanchun Guo ◽  
Qiu Zhong ◽  
Qiang Zhang ◽  
Ahamed Hossain ◽  
...  
Keyword(s):  
Pharmacokinetic Study ◽  
Hdac Inhibitor ◽  
Active Drug ◽  
Hydrolysis Product ◽  
Liver Microsomes ◽  
Tumor Model ◽  
Maximum Plasma ◽  
Metabolic Products

ZL277 is a prodrug of belinostat with enhanced bioavailability and efficacy as a pan histone deacetylase (HDAC) inhibitor. In this study, we investigated the metabolism and pharmacokinetics of ZL277 in liver S9 fractions, liver microsomes, liver cytosol, and in mice. Metabolic products were identified and quantified by a combination of liquid chromatography and tandem mass spectrometry. The in vitro metabolic profile of ZL277 includes ZL277-B(OH)2-452, the major oxidative metabolite ZL277-OH-424, the active ingredient belinostat, belinostat amide, belinostat acid, and methylated belinostat in liver S9 fractions. Both ZL277-OH-424 and belinostat underwent further glucuronidation in liver microsome, whereas only ZL277-OH-424, but not belinostat, underwent some level of sulfation in rat liver cytosols. These metabolites were examined in plasma and in a breast tumor model in vivo. They were also examined in urine and feces from mice treated with ZL277. The pharmacokinetic study of ZL277 showed the parameters of active drug belinostat with a half-life (t1/2) of 10.7 h, an area under curve value (AUC) of 1506.9 ng/mL*h, and a maximum plasma concentration (Cmax) of 172 ng/mL, reached 3 h after a single dose of 10 mg/kg. The hydrolysis product of the prodrug, ZL277-B(OH)2-452 showed an AUC of 8306 ng/mL*h and Cmax of 931 ng/mL 3 h after drug administration.

Effects of Ginkgo biloba Extract Ingestion on the Pharmacokinetics of Talinolol in Healthy Chinese Volunteers

2009 ◽  
Vol 43 (5) ◽  
pp. 944-949 ◽  
Author(s):  
Lan Fan ◽  
Gong-You Tao ◽  
Guo Wang ◽  
Yao Chen ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Ginkgo Biloba ◽  
High Performance ◽  
Plasma Concentrations ◽  
Ginkgo Biloba Extract ◽  
Maximum Plasma ◽  
Time Curve ◽  
P Glycoprotein

Background Ginkgo biloba extract (GBE), the best selling herbal medicine in the world, has been reported to inhibit P-glycoprotein in vitro. However, the effects of GBE on P-glycoprotein activity in humans have not been clarified. Objective To investigate the effects of single and repeated GBE ingestion on the oral pharmacokinetics of talinolol, a substrate drug for P-glycoprotein in humans. Methods Ten unrelated healthy male volunteers were selected to participate in a 3-stage sequential study. Plasma concentrations of talinolol from 0 to 24 hours were measured by high-performance liquid chromatography after talinolol 100 mg was administrated alone, with a single oral dose of GBE (120 mg), and after 14 days of repeated GBE ingestion (360 mg/day). Results A single oral dose of GBE did not affect the pharmacokinetics of talinolol. Repeated ingestion of GBE increased the talinolol maximum plasma concentration (Cmax) by 36% (90% CI 10 to 68; p = 0.025), the area under the concentration-time curve (AUC)0-24 by 26% (90% CI 11 to 43; p = 0.008) and AUC0-∞ by 22% (90% CI 8 to 37; p = 0.014), respectively, without significant changes in elimination half-life and the time to Cmax. Conclusions Our results suggest that long-term use of GBE significantly influenced talinolol disposition in humans, likely by affecting the activity of P-glycoprotein and/or other drug transporters.

Inhibitory effect of silybin on pharmacokinetics of imatinib in vivo and in vitro

2014 ◽  
Vol 92 (11) ◽  
pp. 961-964 ◽  
Author(s):  
Li Wang ◽  
Zhe Wang ◽  
Meng-ming Xia ◽  
Ying-ying Wang ◽  
Hai-yun Wang ◽  
...  
Keyword(s):  
Single Dose ◽  
Rat Liver ◽  
Liver Microsome ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Rat Liver Microsomes ◽  
Multiple Doses

The objective of this work was to investigate the effect of orally administered silybin on the pharmacokinetics of imatinib in rats and the metabolism of imatinib in human liver microsome and rat liver microsomes. Eighteen healthy male SD rats were randomly divided into 3 groups: group A (control group), group B (received multiple doses of 50 mg·kg−1 silybin for 15 consecutive days), and group C (received a single dose of 50 mg·kg−1 silybin). A single dose of imatinib was administered orally 30 min after administration of silybin (50 mg·kg−1). Imatinib plasma levels were measured by UPLC-MS/MS, and pharmacokinetic parameters were calculated by DAS 3.0 software (Bontz Inc., Beijing, China). In addition, human and rat liver microsome were performed to determine the effects of silybin metabolism of imatinib in vitro. The multiple doses or single dose of 50 mg·kg−1 silybin significantly decreased the area under the curve (0-t) of imatinib (p < 0.01). And the half-life (t1/2) of imatinib is significantly increased (p < 0.05 and p < 0.01, respectively). Also, silybin showed inhibitory effect on human and rat microsomes, the IC50 of silybin were 26.42 μmol·L−1 and 49.12 μmol·L−1 in human and rat liver microsomes, respectively. These results indicate that more attention should be paid to when imatinib is administrated combined with silybin.

scholarly journals Inhibition and Induction by Poziotinib of Different Rat Cytochrome P450 Enzymes In Vivo and in an In Vitro Cocktail Method

2021 ◽  
Vol 11 ◽  
Author(s):  
Jinhui Wang ◽  
Feifei Chen ◽  
Hui Jiang ◽  
Jia Xu ◽  
Deru Meng ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Rat Liver ◽  
Clinical Investigation ◽  
Liver Microsomes ◽  
Pharmacokinetic Parameters ◽  
Rat Liver Microsomes ◽  
Cytochrome P450 Enzymes ◽  
Significant Difference

Poziotinib is an orally active, irreversible, pan-HER tyrosine kinase inhibitor used to treat non-small cell lung cancer, breast cancer, and gastric cancer. Poziotinib is currently under clinical investigation, and understanding its drug-drug interactions is extremely important for its future development and clinical application. The cocktail method is most suitable for evaluating the activity of cytochrome P450 enzymes (CYPs). As poziotinib is partially metabolized by CYPs, cocktail probes are used to study the interaction between drugs metabolized by each CYP subtype. Midazolam, bupropion, dextromethorphan, tolbutamide, chlorzoxazone, phenacetin, and their metabolites were used to examine the effects of poziotinib on the activity of cyp1a2, 2b1, 2d1, 2c11, 2e1, and 3a1/2, respectively. The in vitro experiment was carried out by using rat liver microsomes (RLMs), whereas the in vivo experiment involved the comparison of the pharmacokinetic parameters of the probes after co-administration with poziotinib to rats to those of control rats treated with only probes. UPLC-MS/MS was used to detect the probes and their metabolites in rat plasma and rat liver microsomes. The in vitro results revealed that the half-maximal inhibitory concentration values of bupropion and tolbutamide in RLMs were 8.79 and 20.17 μM, respectively, indicating that poziotinib showed varying degrees of inhibition toward cyp2b1 and cyp2c11. Poziotinib was a competitive inhibitor of cyp2b1 and cyp2c11, with Ki values of 16.18 and 17.66 μM, respectively. No time- or concentration-dependence of inhibition by poziotinib was observed toward cyp2b1 and cyp2c11 in RLMs. Additionally, no obvious inhibitory effects were observed on the activity of cyp1a2, cyp2d1, cyp2e1, and cyp3a1/2. In vivo analysis revealed that bupropion, tolbutamide, phenacetin, and chlorzoxazone showed significantly different pharmacokinetic parameters after administration (p &lt; 0.05); there was no significant difference in the pharmacokinetic parameters of dextromethorphan and midazolam. These results show that poziotinib inhibited cyp2b1 and cyp2c11, but induced cyp1a2 and cyp2e1 in rats. Thus, poziotinib inhibited cyp2b1 and cyp2c11 activity in rats, suggesting the possibility of interactions between poziotinib and these CYP substrates and the need for caution when combining them in clinical settings.

scholarly journals Pharmacokinetic Study of Modafinil in Relation to Gender and Ethnicity in Healthy Young Chinese Volunteers

2010 ◽  
Vol 13 (3) ◽  
pp. 443 ◽  
Author(s):  
Tao Guo ◽  
Longshan Zhao ◽  
Dong-Ya Xia
Keyword(s):  
Body Weight ◽  
Oral Dose ◽  
High Performance ◽  
Area Under The Curve ◽  
Total Body Weight ◽  
Apparent Volume ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Significant Difference ◽  
Total Body

Purpose. The pharmacokinetics of modafinil were investigated in relation to gender and ethnicity in healthy young volunteers from Han, Mongolian, Korean, Uygur and Hui ( n = 10/group) following administration of a single 200 mg oral dose. Methods. Blood samples were collected over 48 h for the determination of plasma levels of modafinil and its acid metabolite by High performance liquid chromatography with an ultraviolet detector. Pharmacokinetic parameters were evaluated using noncompartmental methods. Results. Modafinil was well tolerated and safe at a single oral dose of 200 mg. All participants reported adverse events, none of which was serious or unexpected. The maximum plasma concentration (Cmax) and area under the curve for modafinil concentration versus time, which was extrapolated to infinity (AUC0-∞), were higher in women compared to men (p < 0.01). No gender-based difference was noted in the total body weight-normalized modafinil oral clearance. The total body weight-normalized modafinil apparent volume of distribution and the t1/2 was found to exhibit an ethnicity-based significant difference. Conclusion. The results of the current study suggest that there might be pharmacokinetic differences related to gender and ethnicity in the pharmacokinetics of modafinil.

scholarly journals Pharmacokinetic Interaction between Nevirapine and Nortriptyline in Rats: Inhibition of Nevirapine Metabolism by Nortriptyline

2014 ◽  
Vol 58 (12) ◽  
pp. 7041-7048 ◽  
Author(s):  
Iris Usach ◽  
Virginia Melis ◽  
Patricia Gandía ◽  
José-Esteban Peris
Keyword(s):  
Plasma Concentrations ◽  
Pharmacokinetic Interaction ◽  
Hepatic Metabolism ◽  
Transcriptase Inhibitor ◽  
Tricyclic Antidepressant ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Hepatic Microsomes

ABSTRACTOne of the most frequent comorbidities of HIV infection is depression, with a lifetime prevalence of 22 to 45%. Therefore, it was decided to study a potential pharmacokinetic interaction between the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP) and the tricyclic antidepressant nortriptyline (NT). NVP and NT were administered to rats either orally, intraduodenally, or intravenously, and the changes in plasma levels and pharmacokinetic parameters were analyzed. Experiments with rat and human hepatic microsomes were carried out to evaluate the inhibitory effects of NT on NVP metabolism. NVP plasma concentrations were significantly higher when this drug was coadministered with NT. The maximum plasma concentrations of NVP were increased 2 to 5 times and the total plasma clearance was decreased 7-fold in the presence of NT. However, statistically significant differences in the pharmacokinetic parameters of NT in the absence and presence of NVP were not found.In vitrostudies with rat and human hepatic microsomes confirmed the inhibition of NVP hepatic metabolism by NT in a concentration-dependent way, with the inhibition being more intense in the case of rat microsomes. In conclusion, a pharmacokinetic interaction between NVP and NT was detected. This interaction was a consequence of the inhibition of hepatic metabolism of NVP by NT.In vivohuman studies are required to evaluate the effects of this interaction on the pharmacokinetics of NVP before it can be taken into account for patients receiving NVP.

In vitro metabolism of a new cardioprotective agent, KR-33028 in the human liver microsomes and cryopreserved human hepatocytes

2005 ◽  
Vol 28 (11) ◽  
pp. 1287-1292 ◽  
Author(s):  
Hyojin Kim ◽  
Yune -Jung Yoon ◽  
Hyunmi Kim ◽  
Eun -Young Cha ◽  
Hye Suk Lee ◽  
...  
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Human Hepatocytes ◽  
Human Liver Microsomes ◽  
In Vitro Metabolism

scholarly journals Mertansine Inhibits mRNA Expression and Enzyme Activities of Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyltransferases in Human Hepatocytes and Liver Microsomes

Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 220
Author(s):  
Won-Gu Choi ◽  
Ria Park ◽  
Dong Kyun Kim ◽  
Yongho Shin ◽  
Yong-Yeon Cho ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Enzyme Activities ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Hepatocytes ◽  
Cytochrome P450s ◽  
Human Liver Microsomes ◽  
Mrna Levels ◽  
Tubulin Inhibitor

Mertansine, a tubulin inhibitor, is used as the cytotoxic component of antibody–drug conjugates (ADCs) for cancer therapy. The effects of mertansine on uridine 5′-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes and its effects on the mRNA expression of cytochrome P450s (CYPs) and UGTs in human hepatocytes were evaluated to assess the potential for drug–drug interactions (DDIs). Mertansine potently inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-β-glucuronidation, and UGT1A4-catalyzed trifluoperazine N-β-d-glucuronidation, with Ki values of 13.5 µM, 4.3 µM, and 21.2 µM, respectively, but no inhibition of UGT1A6, UGT1A9, and UGT2B7 enzyme activities was observed in human liver microsomes. A 48 h treatment of mertansine (1.25–2500 nM) in human hepatocytes resulted in the dose-dependent suppression of mRNA levels of CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, UGT1A1, and UGT1A9, with IC50 values of 93.7 ± 109.1, 36.8 ± 18.3, 160.6 ± 167.4, 32.1 ± 14.9, 578.4 ± 452.0, 539.5 ± 233.4, 856.7 ± 781.9, and 54.1 ± 29.1 nM, respectively, and decreased the activities of CYP1A2-mediated phenacetin O-deethylase, CYP2B6-mediated bupropion hydroxylase, and CYP3A4-mediated midazolam 1′-hydroxylase. These in vitro DDI potentials of mertansine with CYP1A2, CYP2B6, CYP2C8/9/19, CYP3A4, UGT1A1, and UGT1A9 substrates suggest that it is necessary to carefully characterize the DDI potentials of ADC candidates with mertansine as a payload in the clinic.

scholarly journals Long-term maintenance of functional primary human hepatocytes in 3D gelatin matrices produced by solution blow spinning

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mariliis Klaas ◽  
Kaidi Möll ◽  
Kristina Mäemets-Allas ◽  
Mart Loog ◽  
Martin Järvekülg ◽  
...  
Keyword(s):  
Liver Tissue ◽  
Drug Testing ◽  
Three Dimensional ◽  
Human Hepatocytes ◽  
Drug Induced ◽  
Human Liver Tissue ◽  
Drug Induced Liver Injury ◽  
Solution Blow Spinning

AbstractSolution blow spinning (SBS) has recently emerged as a novel method that can produce nano- and microfiber structures suitable for tissue engineering. Gelatin is an excellent precursor for SBS as it is derived mainly from collagens that are abundant in natural extracellular matrices. Here we report, for the first time the successful generation of 3D thermally crosslinked preforms by using SBS from porcine gelatin. These SBS mats were shown to have three-dimensional fibrous porous structure similar to that of mammalian tissue extracellular matrix. In pharma industry, there is an urgent need for adequate 3D liver tissue models that could be used in high throughput setting for drug screening and to assess drug induced liver injury. We used SBS mats as culturing substrates for human hepatocytes to create an array of 3D human liver tissue equivalents in 96-well format. The SBS mats were highly cytocompatible, facilitated the induction of hepatocyte specific CYP gene expression in response to common medications, and supported the maintenance of hepatocyte differentiation and polarization status in long term cultures for more than 3 weeks. Together, our results show that SBS-generated gelatin scaffolds are a simple and efficient platform for use in vitro for drug testing applications.

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