Study on the metabolic mechanism of chiral inversion of S-Mandelic acid in vitro

Chirality ◽  
2011 ◽  
Vol 24 (1) ◽  
pp. 86-95 ◽  
Author(s):  
Ling-Bo Gao ◽  
Jin-Zhao Wang ◽  
Tong-Wei Yao ◽  
Su Zeng
Keyword(s):  
Mandelic Acid ◽  
Chiral Inversion ◽  
Metabolic Mechanism

scholarly journals In vitro genotoxicity evaluation and metabolic study of residual glutaraldehyde in animal-derived biomaterials

2020 ◽  
Vol 7 (6) ◽  
pp. 619-625
Author(s):  
Jianfeng Shi ◽  
Huan Lian ◽  
Yuanli Huang ◽  
Danmei Zhao ◽  
Han Wang ◽  
...  
Keyword(s):  
Metabolic Activation ◽  
Chemical Toxicity ◽  
Major Health ◽  
Mouse Lymphoma Assay ◽  
Metabolic Mechanism ◽  
Mutagenic Effects ◽  
Mouse Lymphoma ◽  
General Balance ◽  
In Vitro Genotoxicity

Abstract Glutaraldehyde (GA) is an important additive that is mainly used in animal-derived biomaterials to improve their mechanical and antimicrobial capacities. However, GA chemical toxicity and the metabolic mechanism remain relatively unknown. Therefore, residual GA has always been a major health risk consideration for animal-derived medical devices. In this study, extracts of three bio-patches were tested via the GA determination test and mouse lymphoma assay (MLA). The results showed that dissolved GA was a potential mutagen, which could induce significant cytotoxic and mutagenic effects in mouse lymphoma cells. These toxic reactions were relieved by the S9 metabolic activation (MA) system. Furthermore, we confirmed that GA concentration decreased and glutaric acid was generated during the catalytic process. We revealed GA could be oxidized via cytochrome P450 which was the main metabolic factor of S9. We found that even though GA was possibly responsible for positive reactions of animal-derived biomaterials’ biocompatibility evaluation, it may not represent the real situation occurring in human bodies, owing to the presence of various detoxification mechanisms including the S9 system. Overall, in order to achieve a general balance between risk management and practical application, rational decisions based on comprehensive analyses must be considered.

The enantioselective metabolic mechanism of quizalofop-ethyl and quizalofop-acid enantiomers in animal: protein binding, intestinal absorption, and in vitro metabolism in plasma and the microsome

RSC Advances ◽  
2016 ◽  
Vol 6 (101) ◽  
pp. 99003-99009
Author(s):  
Yiran Liang ◽  
Peng Wang ◽  
Donghui Liu ◽  
Jing Zhan ◽  
Mai Luo ◽  
...  
Keyword(s):  
Serum Albumin ◽  
Protein Binding ◽  
Intestinal Absorption ◽  
Liver Microsome ◽  
Animal Protein ◽  
In Vitro Metabolism ◽  
Everted Gut Sac ◽  
Metabolic Mechanism ◽  
Quizalofop Ethyl

The effects of protein binding (pepsin, trypsin and serum albumin), intestinal absorption (everted gut sac), and degradation (plasma, liver microsome and cytosol) on the enantioselectivity of quizalofop-ethyl in animals were studiedin vitro.

Metabolic chiral inversion of flurbiprofen-CoA In vitro

1991 ◽  
Vol 42 (1) ◽  
pp. R1-R4 ◽  
Author(s):  
David J. Porubek ◽  
Susan M. Sanins ◽  
Jeffrey R. Stephens ◽  
Mark P. Grillo ◽  
David G. Kaiser ◽  
...  
Keyword(s):  
Chiral Inversion

Pharmacokinetics of Darolutamide in Mouse – Assessment of the Disposition of the Diastereomers, Key Active Metabolite and Interconversion Phenomenon: Implications to Cancer Patients

2020 ◽  
Vol 14 ◽  
Author(s):  
Neeraj Kumar Saini ◽  
Bhavesh Babulal Gabani ◽  
Umesh Todmal ◽  
Suresh P Sulochana ◽  
Vinay Kiran ◽  
...  
Keyword(s):  
Protein Binding ◽  
Liver Microsomes ◽  
Stability Study ◽  
Pharmacokinetic Data ◽  
Chiral Inversion ◽  
Tissue Samples ◽  
Clinical Pharmacokinetics ◽  
Oral And Intravenous Dosing

Background: Darolutamide is recently approved for the treatment of non-metastatic castrate resistance prostate cancer. Hitherto, no stereoselective pharmacokinetic data has been published pertaining to darolutamide and its diastereomers in animals or humans. The key aims of the experiment were to examine darolutamide, S,S-darolutamide and S,R-darolutamide with respect to (a) assessment of in vitro stability and protein binding (b) characterization of in vivo oral and intravenous pharmacokinetics in mice. Method: In vitro (liver microsomes stability and protein binding) and in vivo experiments (oral/intravenous dosing to mice) were carried out using darolutamide, S,S-darolutamide and S,R-darolutamide. Besides, tissue levels of darolutamide, S,S-darolutamide and S,R-darolutamide were measured following oral and intravenous dosing. Appropriate plasma/tissue samples served to determine the pharmacokinetics of various analytes in mice. Liquid chromatography in tandem with mass spectrometry procedures enabled the delineation of the plasma pharmacokinetics, in vitro and tissue uptake data of the various analytes. Results: Chiral inversion was absent in the metabolic stability study. However, darolutamide showed profound stereoselectivity (S,Sdarolutamide greater than S,R-darolutamide) after either intravenous or oral dosing. S,R-darolutamide but not S,S-darolutamide showed conversion to its antipode post oral and intravenous dosing to mice. Regardless of oral or intravenous dosing, active keto darolutamide formation was evident after administration of darolutamide, S,S-darolutamide or S,R- darolutamide. Tissue data supported the observations in plasma; however, tissue exposure of the various darolutamide, S,S-darolutamide and S,R-darolutamide were much lower as compared to plasma. Conclusion: In lieu of the human pharmacokinetic data, although the administration of diastereomeric darolutamide was justified, it is proposed to delineate the clinical pharmacokinetics of S,R-darolutamide and S,S-darolutamide relative to darolutamide in future clinical pharmacology studies.

Thin-layer chromatographic and polarimetric investigation of the oscillatory in-vitro chiral inversion ofS-(+)-ketoprofen

2008 ◽  
Vol 21 (5) ◽  
pp. 349-353 ◽  
Author(s):  
Mieczysław Sajewicz ◽  
Monika Gontarska ◽  
Dorota Kronenbach ◽  
Teresa Kowalska
Keyword(s):  
Thin Layer ◽  
Chiral Inversion

scholarly journals Polyurea Dendrimer Folate-Targeted Nanodelivery of l-Buthionine Sulfoximine as a Tool to Tackle Ovarian Cancer Chemoresistance

Antioxidants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 133 ◽  
Author(s):  
Adriana Cruz ◽  
Pedro Mota ◽  
Cristiano Ramos ◽  
Rita F. Pires ◽  
Cindy Mendes ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Buthionine Sulfoximine ◽  
Ovarian Cancer Cells ◽  
Metabolic Remodeling ◽  
Metabolic Mechanism ◽  
In Vitro Inhibition ◽  
New Formulation ◽  
Cancer Chemoresistance

Ovarian cancer is a highly lethal disease, mainly due to chemoresistance. Our previous studies on metabolic remodeling in ovarian cancer have supported that the reliance on glutathione (GSH) bioavailability is a main adaptive metabolic mechanism, also accounting for chemoresistance to conventional therapy based on platinum salts. In this study, we tested the effects of the in vitro inhibition of GSH synthesis on the restoration of ovarian cancer cells sensitivity to carboplatin. GSH synthesis was inhibited by exposing cells to l-buthionine sulfoximine (l-BSO), an inhibitor of γ-glutamylcysteine ligase (GCL). Given the systemic toxicity of l-BSO, we developed a new formulation using polyurea (PURE) dendrimers nanoparticles (l-BSO@PUREG4-FA2), targeting l-BSO delivery in a folate functionalized nanoparticle.

Simultaneous assay of four stereoisomers of diltiazem hydrochloride. Application to in vitro chiral inversion studies

1995 ◽  
Vol 41 (7-8) ◽  
pp. 450-454 ◽  
Author(s):  
K. Ishii ◽  
K. Minato ◽  
H. Nakai ◽  
T. Sato
Keyword(s):  
Diltiazem Hydrochloride ◽  
Chiral Inversion

Simultaneous assay of four stereoisomers of diltiazem hydrochloride. Application to in vitro chiral inversion studies

1995 ◽  
Vol 41 (5-6) ◽  
pp. 450-454 ◽  
Author(s):  
K. Ishii ◽  
K. Minato ◽  
H. Nakai ◽  
T. Sato
Keyword(s):  
Diltiazem Hydrochloride ◽  
Chiral Inversion

scholarly journals A study on the chiral inversion of mandelic acid in humans

2014 ◽  
Vol 12 (34) ◽  
pp. 6737-6744 ◽  
Author(s):  
Maksims Yevglevskis ◽  
Catherine R. Bowskill ◽  
Chloe C. Y. Chan ◽  
Justin H.-J. Heng ◽  
Michael D. Threadgill ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Mandelic Acid ◽  
Chiral Inversion ◽  
Separate Pathway

Mandelic acid1undergoes uni-directional chiral inversion in mammalian cells by a separate pathway to that of Ibuprofen3.

Stereoselective Pharmacokinetics and Chiral Inversions of Some Chiral Hydroxy Group Drugs

2020 ◽  
Vol 21 (15) ◽  
pp. 1632-1644
Author(s):  
Fuxin Chen ◽  
Qiaoxiu Bai ◽  
Qingfeng Wang ◽  
Suying Chen ◽  
Xiaoxian Ma ◽  
...  
Keyword(s):  
Hydroxy Group ◽  
Complex Problem ◽  
Hydroxyl Group ◽  
Key Factors ◽  
Chiral Inversion ◽  
Chiral Drugs ◽  
Chiral Transformation ◽  
Stereoselective Pharmacokinetics

Background: Chiral safety, especially chiral drug inversion in vivo, is the top priority of current scientific research. Medicine researchers and pharmacists often ignore that one enantiomer will be converted or partially converted to another enantiomer when it is ingested in vivo. So that, in the context that more than 50% of the listed drugs are chiral drugs, it is necessary and important to pay attention to the inversion of chiral drugs. Methods: The metabolic and stereoselective pharmacokinetic characteristics of seven chiral drugs with one chiral center in the hydroxy group were reviewed in vivo and in vitro including the possible chiral inversion of each drug enantiomer. These seven drugs include (S)-Mandelic acid, RS-8359, Tramadol, Venlafaxine, Carvedilol, Fluoxetine and Metoprolol. Results: The differences in stereoselective pharmacokinetics could be found for all the seven chiral drugs, since R and S isomers often exhibit different PK and PD properties. However, not every drug has shown the properties of one direction or two direction chiral inversion. For chiral hydroxyl group drugs, the redox enzyme system may be one of the key factors for chiral inversion in vivo. Conclusion: In vitro and in vivo chiral inversion is a very complex problem and may occur during every process of ADME. Nowadays, research on chiral metabolism in the liver has the most attention, while neglecting the chiral transformation of other processes. Our review may provide the basis for the drug R&D and the safety of drugs in clinical therapy.

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