- Simultaneous GLC determination of clofibrate and clofibric acid in human plasma
-
A simultaneous assay for the detection of clofibrate and its metabolite, clofibric acid [2-(p-chlorophenoxy)-2-methylpropionic acid], is described. This GLC method is rapid and does not require a derivatization step. It is sensitive to 1-μg/ml levels of either compound in biological samples and can be used to characterize the in vivo conversion of clofibrate ester to the free acid.
- Wolf,Zimmerman
-
-
Read Online
- The combination of sesamol and clofibric acid moieties leads to a novel potent hypolipidemic agent with antioxidant, anti-inflammatory and hepatoprotective activity
-
Oxidative stress and inflammation have been considered the main factors in the liver injury of clofibrate (CF). To obtain a novel antihyperlipidemic agent with antioxidant, anti-inflammation and hepatoprotection, the combination of sesamol and clofibric acid moieties was performed and achieved sesamol-clofibrate (CF-Sesamol). CF-Sesamol showed significant hypolipidemia effects in hyperlipidemia mice induced by Triton WR 1339, reducing TG by 38.8% (P 0.01) and TC by 35.1% (P 0.01). CF-Sesamol also displayed an alleviating effect on hepatotoxicity. The hepatic weight and hepatic coefficient were decreased. The amelioration of liver function was observed, such as aspartate and lactate transaminases (AST and ALT), alkaline phosphatase (ALP) and total proteins (TP) levels. Liver histopathological examination showed that hepatocyte necrosis, cytoplasmic loosening, nuclear degeneration and inflammatory cell infiltration reduced obviously by treatment with CF-Sesamol. Related molecular mechanisms on hepatoprotection showed that CF-Sesamol up-regulated Nrf2 and HO-1 expression and down-regulated p-NF-κB p65 expression in hepatic tissues. CF-Sesamol has significant antioxidant and anti-inflammatory effects. Plasma antioxidant enzymes such as SOD and CAT increased, anti-lipid peroxidation product MDA decreased. The expression of TNF-α and IL-6 inflammatory cytokines in liver was significantly lower than that in the CF group. The results indicated that CF-Sesamol exerted more potent antihyperlipidemic effects and definite hepatoprotective activity partly through the Nrf2/NF-κB-mediated signaling pathway.
- Xie, Yundong,Liu, Jiping,Shi, Yongheng,Wang, Bin,Wang, Xiaoping,Wang, Wei,Sun, Meng,Xu, Xinya,Jiang, Haihui,Guo, Min,He, Yiyi,Ren, Cuicui,Cheng, Lifei
-
-
Read Online
- The formation of benzoxacin-3-ones: Via intramolecular Nicholas reactions and synthesis of 8-membered heliannuols
-
The γ-carbonyl cations generated from propargyl ether-Co2(CO)6 complexes undergo intramolecular Nicholas reactions to give dehydrobenzoxacin-3-one-Co2(CO)6 complexes in good yields. Reductive decomplexation and subsequent manipulation allows the synthesis of (±)-heliannuol K methyl ether and the formal syntheses of (±)-heliannuol K, (±)-heliannuol A, and (-)-heliannuol L.
- Green, James R.,St. Onge, Brent
-
supporting information
p. 7152 - 7155
(2021/08/30)
-
- Diester compounds of PPAR protein activator
-
The invention relates to diester compounds of a PPAR protein activator. The compounds are compounds shown in the formula (I) and pharmaceutically acceptable salts, prodrugs and solvates thereof, and apharmaceutical composition comprising the compounds and a synthesis method thereof. Furthermore, the invention relates to pharmaceutical composition comprising the compounds, and the pharmaceutical composition can be used for the prevention or treatment on diseases associated with PPPAR proteins.
- -
-
Paragraph 0056-0064
(2020/12/15)
-
- INHIBITORS TO TARGET HIV-1 NEF-CD80/CD86 INTERACTIONS FOR THERAPEUTIC INTERVENTION
-
The compounds of Formula I, II, and III along with their stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates and hydrates thereof are described in the present disclosure. The said compounds restore immune activation in case of infections or a disease associated with an HIV infection in a subject in need thereof.
- -
-
Paragraph 000169; 000186; 000187; 000189
(2020/03/05)
-
- Piperazine adenosine monophosphate activated protein kinase (AMPK) agonist and medical application thereof
-
The invention discloses a piperazine compound with AMPK agonist activity, and a preparation method and medical application of the piperazine compound. The piperazine compound is a compound shown as aformula (I) (please see the specifications for the formula), and a pharmaceutically acceptable salt or ester or a prodrug or N-oxide or solvate thereof. The compound can be used for preparing drugs for preventing or treating AMPK-mediated diseases.
- -
-
-
- Decarboxylative Giese-Type Reaction of Carboxylic Acids Promoted by Visible Light: A Sustainable and Photoredox-Neutral Protocol
-
We describe herein a transition-metal-free method for the decarboxylative generation of radicals from carboxylic acids and their 1,4-addition to Michael acceptors. The Fukuzumi catalyst (9-mesitylene-10-methylacridinium perchlorate, [Acr-Mes]ClO4) enabled this transformation under visible-light irradiation at room temperature with CO2 as the only byproduct. The scope and limitations of this protocol were examined by using a range of Michael acceptors (15 examples) and carboxylic acids (18 examples). The use of 3-hydroxypivalic acid in this protocol allowed the straightforward formation of a diastereomerically pure δ-lactone. Moreover, when a homoallylic acid was used, a radical cascade reaction took place with the formation of three C–C bonds.
- Ramirez, Nieves P.,Gonzalez-Gomez, Jose C.
-
supporting information
p. 2154 - 2163
(2017/04/24)
-
- Design, synthesis of novel, potent, selective, orally bioavailable adenosine A2A receptor antagonists and their biological evaluation
-
Our initial structure-activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound 25 as a potent and selective A2A adenosine receptor (A2AAdoR) antagonist with reasonable ADME and pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug design approach resulted in discovery of potent and selective adenosine A2A receptor antagonists bearing substituted 1-methylcyclohexyl-carboxamide groups at position 2 of the benzothiazole scaffold and endowed with better solubility and oral bioavailability. Compounds 41 and 49 demonstrated a number of positive attributes with respect to in vitro ADME properties. Both compounds displayed good pharmacokinetic properties with 63% and 61% oral bioavailability, respectively, in rat. Further, compound 49 displayed oral efficacy in 6-OHDA lesioned rat model of Parkinson diseases.
- Basu, Sujay,Barawkar, Dinesh A.,Thorat, Sachin,Shejul, Yogesh D.,Patel, Meena,Naykodi, Minakshi,Jain, Vaibhav,Salve, Yogesh,Prasad, Vandna,Chaudhary, Sumit,Ghosh, Indraneel,Bhat, Ganesh,Quraishi, Azfar,Patil, Harish,Ansari, Shariq,Menon, Suraj,Unadkat, Vishal,Thakare, Rhishikesh,Seervi, Madhav S.,Meru, Ashwinkumar V.,De, Siddhartha,Bhamidipati, Ravi K.,Rouduri, Sreekanth R.,Palle, Venkata P.,Chug, Anita,Mookhtiar, Kasim A.
-
p. 681 - 694
(2017/02/05)
-
- Method for synthesizing clofibrate drug intermediate 2-(4-Chlorophenoxy)-2-methylpropionic acid
-
A method for synthesizing a clofibrate drug intermediate 2-(4-Chlorophenoxy)-2-methylpropionic acid includes the following steps that 0.62 mol of p-chloro phenoxy solution, 300 ml of hexane, 500 ml of sodium sulfite solution and 0.71-0.73 mol of acetamide solution are added into a reaction container provided with a stirrer, a thermometer, a backflow condenser and a dropping funnel, the stirring speed is controlled to be 130-160 rpm, the solution temperature is raised to 60-65 DEG C, 0.75-0.79 mol of 1-bromine-methanediamine solution is added dropwise, reflux is maintained for 90-130 min after addition, an oxalic acid is added to adjust the pH value of the solution to be 4-5, the solution temperature is reduced to 3-7 DEG C, solid is separated out, filtered, washed with a saline solution, propionitrile and ethylenediamine, dehydrated through a dehydrating agent and recrystallized in nitromethane, and crystal of 2-(4-Chlorophenoxy)-2-methylpropionic acid is obtained.
- -
-
Paragraph 0005; 0013; 0014
(2016/11/21)
-
- Pd(II)-catalyzed ortho - Or meta-C-H olefination of phenol derivatives
-
A combination of weakly coordinating auxiliaries and ligand acceleration allows for the development of both ortho- and meta-selective C-H olefination of phenol derivatives. These reactions demonstrate the feasibility of directing C-H functionalizations when functional groups are distal to target C-H bonds. The meta-C-H functionalization of electron-rich phenol derivatives is unprecedented and orthogonal to previous electrophilic substitution of phenols in terms of regioselectivity. These methods are also applied to functionalize α-phenoxyacetic acids, a fibrate class of drug scaffolds.
- Dai, Hui-Xiong,Li, Gang,Zhang, Xing-Guo,Stepan, Antonia F.,Yu, Jin-Quan
-
supporting information
p. 7567 - 7571
(2013/06/27)
-
- Synthesis and preliminary antihyperlipidaemic activities evaluation of andrographolide derivatives
-
Recent studies indicated that andrographolide was a potential antihyperlipidaemic therapeutic agent. In the paper, the synthesis of a series of andrographolide derivatives was described and their antihyperlipidaemic activities were evaluated in vivo. As compared with TG, TC, HDL-C and LDL-C concentrations, some of the derivatives exhibited better antihyperlipidaemic effects than positive control atromide. Therein, compound 6i, which was the most potent compound, could serve as a new lead for further development of antihyperlipidaemic agents.
- Wang, Bin,Tang, Chunlei,Han, Yaodan,Guo, Ruzhou,Qian, Hai,Huang, Wenlong
-
experimental part
p. 293 - 298
(2012/07/30)
-
- AMINE AND ETHER COMPOUNDS WHICH MODULATE THE CB2 RECEPTOR
-
Compounds which modulate the CB2 receptor are disclosed. The compounds are useful for treating CB2 receptor-mediated diseases such as pain.
- -
-
Page/Page column 36-37
(2009/10/18)
-
- N,N-DISUBSTITUTED AMINOALKYLBIPHENYL ANTAGONISTS OF PROSTAGLANDIN D2 RECEPTORS
-
Described herein are compounds that are antagonists of PGD2 receptors. Also described are pharmaceutical compositions that include the compounds described herein, and methods of using such antagonists of PGD2 receptors, alone or in combination with other compounds, for treating respiratory, cardiovascular, and other PGD2-dependent or PGD2-mediated conditions or diseases.
- -
-
Page/Page column 18
(2009/08/16)
-
- Substituted tertiary phosphine Ru(II) organometallics: Catalytic utility on the hydrolysis of etofibrate in pharmaceuticals
-
Some new organometallics of ruthenium(II) of the type [RuCl2(COD)(CO)L] (1a-f) and [RuCl2(COD)L2] (2a-f) (where L is substituted tertiary phosphines), have been synthesized by using precursors [RuCl2(COD)(CO)(CH
- Reddy, P. Muralidhar,Shanker, Kanne,Rohini, Rondla,Sarangapani,Ravinder, Vadde
-
experimental part
p. 1231 - 1237
(2009/02/03)
-
- 2,2,2-TRI-SUBSTITUTED ACETAMIDE DERIVATIVES AS GLUCOKINASE ACTIVATORS, THEIR PROCESS AND PHARMACEUTICAL APPLICATION
-
Compounds of the present disclosure are 2,2,2-tri-substituted acetamide derivatives of formula (I), its polymorphs, stereoisomers, prodrugs, solvates, pharmaceutically acceptable salts and formulations thereof, useful as Glucokinase activator. Processes of their preparation are also described in the disclosure. The disclosure also describes method to characterize partial glucokinase activators.
- -
-
Page/Page column 32-33
(2008/12/07)
-
- Liquid-phase synthesis of 2-methyl-2-aryloxypropanoic acid derivatives from poly(ethylene glycol) supported 2-bromo-2-methylpropanoate
-
An efficient liquid-phase synthesis of 2-methyl-2-aryloxypropanoic acid derivatives with good yields and high purity on soluble polyethylene glycol (PEG) has been developed by treatment of PEG-bound 2-bromo-2-methylpropanoate with phenoxides in the presence of a catalytic amount of NBu4I and KI, and subsequent cleavage from the PEG.
- Huang, Bin,Huang, Pei-Gang,Sheng, Shou-Ri,Wang, Qiu-Ying,Guo, Lei,Jiang, Shao-Hua
-
p. 575 - 578
(2008/02/11)
-
- Water-based biphasic media for exothermic reactions: Green chemistry strategy for the large scale preparation of clofibric acid and analogues
-
A water-based biphasic reaction process has been developed for conducting exothermic reactions without organic solvents. This procedure is rapid, simple, and suitable for small scale synthesis as well as larger (multi-molar) scale reactions. The preparation of several hundred grams of clofibric acid and analogues by this eco-friendly and energy-efficient procedure is described. Smaller amounts of these compounds were prepared by the friction-activated 'Grindstone Chemistry' method described previously.
- Bose, Ajay K.,Manhas, Maghar S.,Ganguly, Subhendu N.,Pednekar, Suhas,Mandadi, Arun
-
p. 3011 - 3013
(2007/10/03)
-
- Improved method for the synthesis of 2-methyl-2-aryloxypropanoic acid derivatives
-
An improved method for the formation of 2-methyl-2-aryloxypropanoic acid derivatives, an important class of compounds for the potential treatment of type II diabetes, is reported. This method offers several advantages over the existing chemistry for this transformation.
- Davis, Roman D.,Fitzgerald, Russ N.,Guo, Jiasheng
-
p. 1959 - 1962
(2007/10/03)
-
- Interaction of γ-glutamyltranspeptidase with clofibryl-S-acyl-glutathione in vitro and in vivo in rat
-
Clofibric acid (CA) is metabolized to chemically reactive acylating products that can transacylate glutathione to form clofibryl-S-acyl-glutathione (CA-SG) in vitro and in vivo. We investigated the first step in the degradation of CA-SG to the mercapturic acid conjugate, clofibryl-S-acyl-N-acetylcysteine (CA-SNAC), which is catalyzed by γ-glutamyltranspeptidase (γ-GT). After γ-GT mediated cleavage of glutamate from CA-SG, the product clofibryl-S-acylcysteinylglycine (CA-S-CG) should undergo an intramolecular rearrangement reaction [Tate, S. S. (1975) FEBS Lett. 54, 319-322] to form clofibryl-N-acyl-cysteinylglycine (CA-N-CG). We performed in vitro studies incubating CA-SG with γ-GT to determine the products formed, and in vivo studies examining the products excreted in urine after dosing rats with CA-SG or CA. Thus, CA-SG (0.1 mM) was incubated with γ-GT (0.1 unit/mL) in buffer (pH 7.4, 25 °C) and analyzed for products formed by reversed-phase HPLC and electrospray mass spectrometry (ESI/MS). Results showed that CA-SG is degraded completely after 6 h of incubation leading to the formation of two products, CA-N-CG and its disulfide, with no detection of CA-S-CG thioester. After 36 h of incubation, only the disulfide remained in the incubation. Treatment of the disulfide with dithiothreitol led to the reappearance of CA-N-CG. ESI/LC/MS analysis of urine (16 h) extracts of CA-SG-dosed rats (200 mg/kg, iv) showed that CA-SG is degraded to CA-N-CG, CA-N-acyl-cysteine (CA-N-C) and their respective S-methylated products. The mercapturic acid conjugate (CA-SNAC) was found as a minor product. dAnalysis of urine extracts from CA-dosed rats (200 mg/kg, ip) resulted in the detection of clofibryl-N-acyl-cysteine (CAN-C), but no evidence for the formation of CA-SNAC was obtained. These in vitro and in vivo experiments indicate that γ-GT mediated degradation of clofibryl-S-acyl-glutathione leads primarily to the formation and excretion of clofibryl-N-acyl-cysteine products rather than the S-acyl-NAC conjugate.
- Grillo,Benet
-
p. 1033 - 1040
(2007/10/03)
-
- Acyloxymethyl as a drug protecting group. Part 5. Kinetics and mechanism of the hydrolysis of tertiary N-acyloxymethylsulfonamides
-
Tertiary acyloxymethylsulfonamides undergo hydrolysis via pH-independent and acid- and base-catalysed processes. Reactions are also buffer catalysed for buffer species with pKa values > ca. 10.5. For the pH-independent pathway, hydrolysis takes place via formation of an N-sulfonyl iminium ion. There is no general-base or nucleophilic catalysis in this region. The mechanism of the acid-catalysed process involves pre-equilibrium protonation of the substrate followed by iminium ion formation. General-acid catalysis is not observed. The base-catalysed pathway involves the normal BAc2 mechanism of ester hydrolysis. The buffer-catalysed reaction gives rise to a curved Bronsted plot, with β values of 1.6 and 0.25 for nucleophiles with pKa values 13, respectively. This is indicative of nucleophilic catalysis associated with a change in rate-limiting step from formation of the tetrahedral intermediate for buffer species with pKa > 13 to decomposition of the tetrahedral intermediate for buffer species with pKa f, and atomic charges, q, for acyloxymethyl- and chloromethyl-sulfonamides and amides and their derived iminium ions were performed. These reveal that (1) iminium formation from the sulfonamide series is thermodynamically slightly favoured, and (2) the charge difference at the nitrogen atom, ΔqN, between the neutral molecule and the iminium ion is similar for both sulfonamides and amides.
- Lopes, Francisca,Moreira, Rui,Iley, Jim
-
p. 431 - 439
(2007/10/03)
-
- Cleavage of tertiary amidomethyl ester prodrugs of carboxylic acids by rat liver homogenates
-
The hydrolysis of tertiary amidomethyl ester prodrugs of carboxylic acids by rat liver homogenates is reported. Amidomethyl esters are rapidly and quantitatively converted to the corresponding acid and secondary amide. Reactivity is inversely dependent upon the molar refractivity and lipophilicity of the ester, as well as with steric bulk in the carboxylic acid moiety. In contrast to chemical and plasma hydrolyses, no dependence upon the pK(a) of the carboxylate leaving group was observed, nor was there any dependence upon the amide N-substituent. The rate of decomposition was inhibited by the carboxylesterase inhibitor eserine but not by the cytochrome P450 inhibitor SKF-525A, indicating the involvement of esterases in the hydrolysis reaction. These results indicate that amidomethyl esters may be expected to be readily cleaved in vivo. Copyright (C) 1999 Elsevier Science B.V.
- Iley, Jim,Mendes, Eduarda,Moreira, Rui,Souza, Sofia
-
p. 201 - 205
(2007/10/03)
-
- A simple synthetic route to 3-phenoxybenzyl 2-methyl-2-(p-substituted phenoxy and thiophenoxy/naphthoxy)propyl ethers, structurally related to ethofenoprox
-
Some 3-phenoxybenzyl 2-methyl-2-(p-substituted phenoxy and thiophenoxy/naphthoxy)propyl ethers (8), bearing close structural resemblance to the powerful insecticide MTI-500 have been synthesised by a simple route for evaluating their insecticidal properties.
- Kumaran, G.,Kulkarni, G. H.
-
p. 168 - 170
(2007/10/02)
-
- Presynaptic cholinergic modulators as potent cognition enhancers and analgesic drugs. 2. 2-Phenoxy-, 2-(phenylthio)-, and 2-(phenylamino)alkanoic acid esters
-
Further modifications of the leads ((R)-(+)-hyoscyamine and (p- chlorophenyl)propionic acid α-tropanyl ester), which show analgesic and nootropic activities as a consequence of increased central presynaptic ACh release, are reported. 2-Phenoxy- and 2-(phenylthio)alkanoic acid esters showed the best results. Several members of these classes possess analgesic properties which are comparable to that of morphine and at the same time are able to reverse dicyclomine-induced amnesia. Confirmation was found that the mechanism of action is due to an increase in ACh release at central muscarinic synapses and that both auto- and heteroreceptors controlling ACh release are very likely involved. According to the results obtained with (R)- (+)-hyoscyamine, analgesic activity is stereochemistry dependent, since the R-(+)-enantiomers are always more efficacious than the corresponding S-(-)- ones. On the basis of their potency and acute toxicity, compounds (±)-28 (SM21) and (±)-42 (SM32) were selected for further study.
- Gualtieri,Bottalico,Calandrella,Dei,Giovannoni,Mealli,Romanelli,Scapecchi,Teodori,Galeotti,Ghelardini,Giotti,Bartolini
-
p. 1712 - 1719
(2007/10/02)
-
- Prodrug derivatives of carboxylic acid drugs
-
Novel ester derivatives of carboxylic acid medicaments of formula (I), wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integrer from 1 to 3, and R1 and R2 are the same or different and are selected from a group consisting of an alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may be unsubstituted or substituted, or R1 and R2 together with the N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which heterocyclic group may be substituted. These compounds are highly biolabile prodrug forms of the corresponding carboxylic acid compounds and are highly susceptible to undergoing enzymatic hydrolysis in vivo whereas they are highly stable in aqueous solution. The novel derivatives are less irritating to mucosa than the parent carboxylic acids and may provide an improved bio-availability of the drugs.
- -
-
-
- Pyridylthio-acylanilide herbicides
-
Novel herbicidally active pyridylthio-acylanilides of the formula STR1 in which R1, R2 and R3, independently of one another, represent hydrogen, halogen, cyano or trifluoromethyl or alkyl, alkoxy and alkylthio having 1 to 4 carbon atoms in each case, R4 represents halogen, methyl or methoxy, n represents a number 0, 1 or 2, z represents the group (Ia) STR2 or the group (Ib) STR3 where X represents oxygen, sulphur, an N--R10 or N--O--R11 group, or X and Rg tpgether represent the STR4 radical, and the other radicals can have various meanings. Intermediates of the formulae STR5 are also new.
- -
-
-
- ipso Nitration in p-halophenyl ethers
-
Addition of nitronium ion ipso to halogen occurs on nitration of the p-haloanisoles in acetic anhydride at -60 deg C.In the cases of p-fluoro- and p-chloro-anisole, addition of the nitronium ion is reversible and only small amounts of ipso products are obtained.With p-bromoanisole nitrodebromination occurs.When p-halophenyl ethers containing a trapping substituent, e.g., 2-(4-chlorophenoxy)-2-methylpropanoic acid, are used as substrates, substantial amounts of the spiro diene with nitro ipso to halogen, e.g., 3,3-dimethyl-8-chloro-8-nitro-1,4-dioxaspirodeca-6,9-dien-2-one, can be isolated.The results demonstrate that extensive ipso attack at the halogen-substituted position is general in the nitration of p-halophenyl ethers.Key words: ipso nitration, ether, diene, p-haloanisole.
- Clewley, Robin G.,Fischer, Alfred,Henderson, George N.
-
p. 1472 - 1479
(2007/10/02)
-
- Disposition of etofibrate, clofibric and nicotinic acid esters, and their products in dogs
-
Etofibrate, the ethylene glycol diester of clofibric and nicotinic acids, on intravenous infusion into dogs, has a terminal half-life of 2 min. The intermediate half-esters, the nicotinate and the clofibrate, have respective terminal half-lives of 4.6 and 1.7 min and appear fleetingly when etofibrate is administered. In contrast to the 42-h terminal half-life of clofibric acid, the other final transformation product, nicotinic acid, shows saturable or dose-dependent pharmacokinetics in dogs that conform to the Michaelis-Menten equation with a terminal half-life of 4.4 min at low concentrations ( 6.9 μM/kg). Three distinct metabolites of nicotinic acid can be identified and assayed chromatographically in the urine. The partition properties were similar to nicotinic acid. Nicotinic acid is excreted 30% unchanged into urine with a renal clearance of 70 mL/min in 27-kg dogs.
- Garrett,Altmayer
-
p. 295 - 299
(2007/10/02)
-
- Predictions of stability in pharmaceutical preparations XIX: Stability evaluation and bioanalysis of clofibric acid esters by high-pressure liquid chromatography.
-
Specific, sensitive, reversed-phase high-pressure liquid chromatographic assays of clofibric acid esters, clofibrate and etofibrate, and their hydrolysis products, clofibric acid and its monoglycolate and nicotinic acid and its monoglycolate, have been developed in aqueous solution and in biological fluids. Sensitivities of 100 ng/ml of injected mobile phase, a 10-fold increase over existing methods, are reported. Plasma concentrations as low as 200 ng/ml can be analyzed easily in the miscible phase after acetonitrile denaturation. The compounds and their products can be extracted with haloalkane solvents. The extracts were evaporated, reconstituted, and assayed in minimal amounts of mobile phase, resulting in sensitivities of 10 ng/ml of plasma. Conditions are presented that minimize interferences with plasma components. The assay was used to determine the stability of the clofibric acid esters in aqueous solutions, to establish log k-pH profiles at various temperatures, and to evaluate Arrhenius parameters. Hydrolysis was by specific acid-base catalysis. The initial product of etofibrate solvolysis at pH greater than 6 is the monoglycol ester of clofibric acid; at pH less than 3, it is the monoglycol ester of nicotinic acid. Clofibric acid esters are highly unstable to mild alkali (1-3 hr at pH 10 and 30 degrees); even in the estimated pH range of maximum stability, they have half-lives of 100-200 days at 30 degrees. They have half-lives of 4-7 min at 37.5 degrees in fresh dog plasma, and data presented indicate that clofibric acid monoglycolate is an initial product of etofibrate solvolysis.
- Garrett,Gardner
-
-
- Physico-chemical and analytical studies on plafibride
-
Physico-chemical and analytical studies on N-2-(p-chlorophenoxy)-isobutyryl)-N'-morpholinomethylurea (plafibride, ITA 104) are reported. Besides the usual analytical data, spectral (UV, IR, NMR, MS) and chromatographic (HPLC, TLC) properties are described. As to chemico-analytical procedures, ITA 104 is detectable by titrimetric and spectralphotometric methods and by thin-layer chromatography.
- Torres,Ristol,Ribalta
-
p. 1786 - 1790
(2007/10/02)
-
- Metabolism and pharmacokinetics of etofylline clofibrate, a new hypolipidaemic agent
-
Upon investigations on metabolism and pharmacokinetics of 1-(theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methyl-propionate] (etofylline clofibrate, ML 1024, Duolip) is reported. As can be seen from in vivo tests in rats and dogs ML 1024 is cleaved to the metabolites clofibric acid and etofylline. This could be further demonstrated in vitro by incubation with lipases and human serum. The phrmacokinetic parameters of the metabolites after oral application of 2 capsules Duolip, corresponding to 500 mg etofylline clofibrate, were evaluated in 7 healthy volunteers. The serum fluctuations of the main metabolites could be adapted to an open two-compartment model (clofibric acid) and to a one-compartment model (etofylline). The following mean values were found: the invasion half-life is 1 h 4 min for clofibric acid and 1 h 52 min for etofylline. The maximum concentration after approximately 4 h is 22.75 μg/ml for clofibric acid and 6.57 μg/ml for etofylline. The elimination half-life is 12.12 h for clofibric and 4.33 h for etofylline. Via urine 20 mg clofibric acid and 15.7 mg etofylline were excreted within 8 hr. The elimination process after 8 h is not yet terminated.
- Luecker,Wetzelsberger,Erking,Donike
-
p. 2045 - 2053
(2007/10/02)
-