- Conclusive identification of the oxybutynin-hydrolyzing enzyme in human liver
-
The aim of this study was to conclusively determine the enzyme responsible for the hydrolysis of oxybutynin in human liver. Hydrolysis in human liver microsomes (HLMs) and human liver cytosol (HLC) followed Michaelis-Menten kinetics with similar Km values. In recombinant human carboxylesterase (CES)-expressing microsomes, CES1 was much more efficient than CES2 and yielded a Km value more comparable with that found in HLMs or HLC than did CES2. A correlation analysis using a set of individual HLMs, in which both CESs acted independently showed that the hydrolysis rate of oxybutynin, correlated significantly with a CES1 marker reaction, clopidogrel hydrolysis, but not with a CES2 marker reaction, irinotecan (CPT-11) hydrolysis. Chemical inhibition studies using bis-(p-nitrophenyl) phosphate, clopidogrel, nordihydroguaiaretic acid, procainamide, physostigmine, and loperamide revealed that the effects of these compounds in HLMs, HLC, and recombinant CES1-expressing microsomes were similar, whereas those in CES2-expressing microsomes were clearly different. These results strongly suggest that CES1, rather than CES2, is the principal enzyme responsible for the hydrolysis of oxybutynin in human liver. Copyright
- Sato, Yuichiro,Miyashita, Aiji,Iwatsubo, Takafumi,Usui, Takashi
-
-
Read Online
- In Vitro Assessment of Potential for CYP-Inhibition-Based Drug–Drug Interaction Between Vonoprazan and Clopidogrel
-
Background and Objectives: It was recently proposed that CYP-mediated drug–drug interactions (DDIs) of vonoprazan with clopidogrel and prasugrel can attenuate the antiplatelet actions of the latter two drugs. Clopidogrel is metabolized to the pharmacologically active metabolite H4 and its isomers by multiple CYPs, including CYP2C19 and CYP3A4. Therefore, to investigate the possibility of CYP-based DDIs, in vitro metabolic inhibition studies using CYP probe substrates or radiolabeled clopidogrel and human liver microsomes (HLMs) were conducted in this work. Methods: Reversible inhibition studies focusing on the effects of vonoprazan on CYP marker activities and the formation of the [14C]clopidogrel metabolite H4 were conducted with and without pre-incubation using HLMs. Time-dependent inhibition (TDI) kinetics were also measured. Results: It was found that vonoprazan is not a significant direct inhibitor of any CYP isoforms (IC50 ≥ 16?μM), but shows the potential for TDI of CYP2B6, CYP2C19, and CYP3A4/5. This TDI was weaker than the inhibition induced by the corresponding reference inhibitors ticlopidine, esomeprazole, and verapamil, based on the measured potencies (kinact/KI ratio and the R2 value). In a more direct in vitro experiment, vonoprazan levels of up to 10?μM (a 100-fold higher concentration than the plasma Cmax of 75.9?nM after taking 20?mg once daily for 7?days) did not suppress the formation of the active metabolite H4 or other oxidative metabolites of [14C]clopidogrel in a reversible or time-dependent manner. Additionally, an assessment of clinical trials and post-marketing data suggested no evidence of a DDI between vonoprazan and clopidogrel. Conclusions: The body of evidence shows that the pharmacodynamic DDI reported between vonoprazan and clopidogrel is unlikely to be caused by the inhibition of CYP2B6, CYP2C19, or CYP3A4/5 by vonoprazan.
- Nishihara, Mitsuhiro,Yamasaki, Hitomi,Czerniak, Richard,Jenkins, Helen
-
p. 217 - 227
(2018/11/10)
-
- Ginkgolide B Derivative and Preparation Method And Use Thereof
-
Disclosed are a compound as shown in formula I or formula II or a pharmaceutically acceptable salt thereof, wherein R1 is selected from pyrazinyl or substituted pyrazinyl; and R2 is selected from pyrazinyl or substituted pyrazinyl, phenyl or substituted phenyl, alkyl or substituted alkyl.
- -
-
Paragraph 0044
(2019/03/30)
-
- Probucol derivative, preparation method and application thereof
-
The invention relates to the fields of compounds, and specifically relates to a probucol derivative, a preparation method and the application thereof. The probucol derivative has a structure shown asa general formula I. The probucol derivative provided by the invention can be used for prevention and curing of vascular diseases such as diabetes and cardiovascular and cerebrovascular diseases or complications thereof, can be used for reducing blood glucose, reducing blood fat, reducing cholesterol, reducing the weight, reducing triglyceride, resisting inflammation and oxidation and the like effectively, and has a wide application prospect.
- -
-
Paragraph 0348; 0349; 0350; 0351; 0352
(2019/06/17)
-
- Prodrugs of anti-platelet agents
-
The invention relates to the compounds of formula I, formula II, formula Ia, formula IIb or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, formula II, formula Ia, formula IIb and methods for treating or preventing atherothrombosis may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment or management of ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular, cardiovascular diseases and blood clots.
- -
-
-
- A facile solid-phase synthesis of (+)-(S)-clopidogrel
-
Enantiomerically pure (+)-(S)-clopidogrel was prepared by solid-phase synthesis using the commercially available Wang resin. This method offers mild reaction conditions and provides the (+)-(S)-clopidogrel in overall 52% yield over six steps and with optical purity of 98.0% ee. Copyright
- Jung, Kiwon,Kim, Jae-Sun,Kim, Tae-Hyun,Kim, Jinwoong
-
p. 326 - 329
(2013/03/28)
-
- Different hydrolases involved in bioactivation of prodrug-type angiotensin receptor blockers: Carboxymethylenebutenolidase and carboxylesterase 1
-
Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor blocker (ARB). We recently identified carboxymethylenebutenolidase homolog (CMBL) as the responsible enzyme for OM bioactivation in humans. In the present study, we compared the bioactivating properties of OM with those of other prodrug-type ARBs, candesartan cilexetil (CC) and azilsartan medoxomil (AM), by focusing on interspecies differences and tissue specificity. In invitro experiments with pooled tissue subcellular fractions of mice, rats, monkeys, dogs, and humans, substantial OM-hydrolase activities were observed in cytosols of the liver, intestine, and kidney in all the species tested except for dog intestine, which showed negligible activity, whereas lung cytosols showed relatively low activities compared with the other tissues. AM-hydrolase activities were well correlated with the OM-hydrolase activities. In contrast, liver microsomes exhibited the highest CC-hydrolase activity among various tissue subcellular fractions in all the species tested. As a result of Western blot analysis with the tissue subcellular fractions, the band intensities stained with anti-human CMBL and carboxylesterase 1 (CES1) antibodies well reflected OM- and AM-hydrolase activities and CC-hydrolase activity, respectively, in animals and humans. Recombinant human CMBL and CES1 showed significant AM- and CC-hydrolase activities, respectively, whereas CC hydrolysis was hardly catalyzed with recombinant carboxylesterase 2 (CES2). In conclusion, OM is bioactivated mainly via intestinal and additionally hepatic CMBL not only in humans but also in mice, rats, and monkeys, while CC is bioactivated via hepatic CES1 rather than intestinal enzymes, including CES2. AM is a substrate for CMBL. Copyright
- Ishizuka, Tomoko,Yoshigae, Yasushi,Murayama, Nobuyuki,Izumi, Takashi
-
supporting information
p. 1888 - 1895
(2013/11/06)
-
- PROCESS FOR THE SYNTHESIS OF CLOPIDOGREL AND NEW FORMS OF PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
-
The present invention relates to a new process for the preparation of clopidogrel and to new polymorphic forms of clopidogrel salts, to processes for their preparation and to a pharmaceutical formulation containing the new forms.
- -
-
Page/Page column 3; 40-41
(2008/06/13)
-
- Method of Preparing Clopidogrel and Intermediates Used Therein
-
Optically pure clopidogrel can be prepared in a high yield by optically resolving a racemic form of the compound of formula (II) using an optically active amine to form the optically active form of the compound of formula (III) or its acid-addition salt; and methylating the compound of formula (III) or its acid-addition salt.
- -
-
Page/Page column 5
(2008/12/08)
-
- PROCESS FOR HIGH YIELD PRODUCTION OF CLOPIDOGREL BY RACEMIZATION OF RESIDUAL LIQUID
-
The present invention relates to a process for preparing S-(+)-clopidogrel in high yield by means of racemization of filtrate, and particularly to a process comprising (a) conducting an optical resolution by converting racemic carboxylic acid of clopidogrel to diastereomer salt using (+)-cinchonine, (b) preparing carboxylic acid of S-(+)-clopidogrel by extraction using an appropriate solvent under an acidic condition, (c) preparing optically pure S-(+)-clopidogrel by reacting the carboxylic acid of S-(+)-clopidogrel with methanol, wherein a filtrate, which remains after collecting the diastereomer salt as solid precipitates, is recycled after being converted to a racemic carboxylic acid of clopidogrel via racemization under a basic condition, thereby maximizing the yield of S-(+)-clopidogrel.
- -
-
Page/Page column 16; 18-19
(2008/06/13)
-
- PROCESS FOR THE PREPARATION OF (S)-(+)-CLOPIDOGREL ON A SOLID-PHASE
-
The present invention relates to a process for preparing S-(+)-clopidogrel using a solid-phase reaction, and more particularly, to a process for preparing S-(+)- clopidogrel represented by the following formula 1 with high optical and chemical purity by carrying out a series of reactions and purifications more simply by a solid- phase synthetic approach using a polymer support.
- -
-
Page/Page column 19-20
(2010/11/27)
-
- PROCESS FOR THE PREPARATION OF S-(+)-CLOPIDOGREL BY OPTICAL RESOLUTION
-
The present invention relates to a process for the preparation of S-(+)-clopidogrel by an optical resolution and, more particularly, to a process for the preparation of S-(+)-clopidogrel represented by the following formula 1 with high optical purity by converting a clopidogrel racemic carboxylic acid into a diastereomeric salt using a (+)-cinchonine for optical resolution, extracting an S-(+)-clopidogrel carboxylic acid from the diastereomeric salt using a suitable solvent under an acidic condition and then reacting the S-(+)-clopidogrel carboxylic acid with methanol.
- -
-
Page/Page column 8; 14-15; 19
(2008/06/13)
-
- METHOD OF PREPARING CLOPIDOGREL AND INTERMEDIATES USED THEREIN
-
Optically pure clopidogrel can be prepared in a high yield by optically resolving a racemic form of the compound of formula (II) using an optically active amine to form the optically active form of the compound of formula (III) or its acid-addition salt; and methylating the compound of formula (III) or its acid-addition salt.
- -
-
Page/Page column 12-13
(2010/11/25)
-