82768-85-2Relevant academic research and scientific papers
Optimal pH 8.5 to 9 for the hydrolysis of vixotrigine and other basic substrates of carboxylesterase-1 in human liver microsomes
Gu, Chungang,Huang, Jiansheng,Johnson, Joshua L.,Rooney, Michael
, (2022/03/27)
Vixotrigine is a voltage- and use-dependent sodium channel blocker under investigation for the potential treatment of neuropathic pain. One of the major in?vivo metabolic pathways of vixotrigine in humans is the hydrolysis of the carboxamide to form the carboxylic acid metabolite M14. The in?vitro formation of M14 in human hepatocytes was inhibited by the carboxylesterase (CES) inhibitor Bis(4-nitrophenyl) phosphate in a concentration-dependent manner. The hydrolysis reaction was identified to be catalysed by recombinant human CES1b. Initial observation of only trace level formation of M14 in human liver microsomes at pH 7.4 caused us to doubt the involvement of CES1, an enzyme localised at the endoplasmic reticulum and the dominant carboxylesterase in human liver. Further investigation has revealed that optimal pH for the hydrolysis of vixotrigine and two other basic substrates of CES1, methylphenidate and oseltamivir, in human liver microsomes was pH 8.5–9 which is higher than their respective pKa(base), suggesting that neutral form of basic substrates is probably preferred for CES1 catalysis in liver microsomes.
The stability of quinapril hydrochloride - A mixture of amorphous and crystalline forms (QHCl-AC) in solid phase
Stanisz, Beata
, p. 443 - 450 (2007/10/03)
The first-order rate constants and thermodynamic parameters (Ea [kJ · mole-1] = 139.9 for RH=0% and 133.6 for RH=76.4%; ΔH≠[kJ · mole-1] = 137.4 for RH=0% and 131.1 for RH=76.4%; Δ(S≠ [J · (K 1 · mole-1)] = 35.4 for RH=0% and -207.8 for RH=76.4%) for the degradation of quinapril hydrochloride - a mixture of amorphous and crystalline forms (QHC1-AC) in solid state were calculated. The effect of humidity on the stability of QHC1-AC in the humidity range 25.0% to 76% at 363K is described by the equation In k1 = ax + b = (0.058 ± 0.0086) · RH% - (14.19 ± 0.50). Mechanism of degradation of QHC1-AC was investigated at 363 K (relative humidity 76.4%) and 373 K (relative humidity 0%).
Physical characteristics and chemical degradation of amorphous quinapril hydrochloride
Guo, Yushen,Byrn, Stephen R.,Zografi, George
, p. 128 - 143 (2007/10/03)
This study was designed to investigate the relationships between the solid-state chemical instability and physical characteristics of a model drug, quinapril hydrochloride (QHCl), in the amorphous state. Amorphous QHCl samples were prepared by rapid evaporation from dichloromethane solution and by grinding and subsequent heating of the crystalline form. Physical characteristics, including the glass transition temperature and molecular mobility, were determined using differential scanning calorimetry, thermogravimetric analysis, powder x-ray diffractometry, polarizing microscopy, scanning electron microscopy, and infrared spectroscopy. The amorphous form of QHCl, produced by both methods, has a T(g) of 91°C. Isothermal degradation studies showed that cyclization of QHCl occurred at the same rate for amorphous samples prepared by the two methods. The activation energy was determined to be 30 to 35 kcal/mol. The rate of the reaction was shown to be affected by sample weight, dilution through mixing with another solid, and by altering the pressure above the sample. The temperature dependence for chemical reactivity below T(g) correlated very closely with the temperature dependence of molecular mobility. Above T(g), however, the reaction was considerably slower than predicted from molecular mobility. From an analysis of all data, it appears that agglomeration and sintering of particles caused by softening of the solid, particularly above T(g), and a resulting reduction of the particle surface/volume ratio play a major role in affecting the reaction rate by decreasing the rate of removal of the gaseous HCl product. (C) 2000 Wiley-Liss, Inc.
Hydrolytic profile for ester- or amide-linkage by carboxylesterases pI 5.3 and 4.5 from human liver
Takai, Satomi,Matsuda, Ayuka,Usami, Yoshiko,Adachi, Tetsuo,Sugiyama, Tadashi,Katagiri, Yoshihiro,Tatematsu, Masae,Hirano, Kazuyuki
, p. 869 - 873 (2007/10/03)
Carboxylesterases (EC 3.1.1.1) from human liver were purified using Q- Sepharose, Sephadex G-150, isoelectrofocusing and Con A-Sepharose. The calculated molecular mass of the pI 5.3 enzyme was 120 kDa and 61 kDa from the results of Sephadex G-150 gel filtration and SDS-polyacrylamide gel electrophoresis (PAGE), respectively, suggesting that this enzyme is a dimer. On the other hand, carboxylesterase pI 4.5, with a molecular-mass of 64 kDa, was a monomer. The activities of both enzymes were inhibited by typical serine enzyme inhibitors. Amino acid sequence analysis of the purified enzymes pI 5.3 and 4.5 showed high homology with rabbit carboxylesterase form 1 and 2, respectively. The results also suggested that carboxylesterase pI 5.3 is identical to the deduced amino acid sequence from cDNA for HUI, and that carboxylesterase pI 4.5 is identical to the deduced amino acid sequence from the cDNA registered as human carboxylesterase (hCE-2) in GenBank. We first purified carboxylesterase pI 4.5 and investigated its hydrolytic activity upon various drugs. The two enzymes differed in substrate specificity. Prodrugs of angiotensin-converting enzyme inhibitors, such as delapril and imidapril, were converted to active metabolites by carboxylesterase pI 5.3, but not by carboxylesterase pI 4.5. The hydrolysis velocity of temocapril by carboxylesterase pI 5.3 was 12-fold faster than by carboxylesterase pI 4.5. In contrast, aspirin oxybutynin and procaine were hydrolyzed by only carboxylesterase pI 4.5. We also found that an amide- linkage in drugs, except for that in aniracetam was not a good substrate for the two enzymes. Consequently, carboxylesterases pI 5.3 and 4.5 maybe involved in the metabolism of various drugs containing an ester-linkage.
