A method of high performance liquid chromatographic separation of clausenamide enantiomers with chiral-AGP（α_1-acid glycoprotein） stationary phases has been established.The absolute configurations of（-）clausenami...A method of high performance liquid chromatographic separation of clausenamide enantiomers with chiral-AGP（α_1-acid glycoprotein） stationary phases has been established.The absolute configurations of（-）clausenamide and（＋）clausenamide are 3S, 4R,5R,6S and 3R,4S,5S,6R,respectively.The present method has been used to analyze the（-）clausenamide and（＋）clausenamide and its analogues such as the major metabolite and synthetic derivatives of clausenamide.展开更多
Aim The present study developed a CYP3A4-expressed Caco-2 monolayer model at which effects of the efflux-metabolism alliance on the transport and uptake of clausenamide（CLA） enantiomers as CYP3A4 substrates were inv...Aim The present study developed a CYP3A4-expressed Caco-2 monolayer model at which effects of the efflux-metabolism alliance on the transport and uptake of clausenamide（CLA） enantiomers as CYP3A4 substrates were investigated. The apparent permeability coefficients （Papp） of （ - ） and （ ＋ ）CLA were higher in the ab- sorptive direction than those in the secretory direction with efflux ratios（ER） of 0. 709 ± 0.411 and 0. 867± 0. 250 （ Х10^-6 -1 cm · s ）, respectively. Their bidirectional transports were significantly reduced by （75.6 ± 87.5）% af- ter treatment with verapamil （ a P-glycoprotein inhibitor） that increased the rate of metabolism by CYP3 A4, whereas the CYP3A4 inhibitor ketoconazole treatment markedly enhanced the basolateral to apical flux of （ - ） and （ ＋ ） CLA with ERs being 2. 934 ± 1. 432 and 1. 877 ± 0. 148 （ Х 10^-6 cm/s） respectively. These changes could be blocked by the duel CYP3A4/P-glycoprotein inhibitor cyclosporine A, consequently, Papp values for CLA enanti- omers in both directions were significantly greater than those obtained by using verapamil or ketoconazole, and their ERs were similar to those following （ - ） or （ ＋ ）-isomer treatment alone. Furthermore, the uptake of （ - ）CLA was more than that of （ ＋ ）CLA in the transfected cells. Incubation with ketoeonazole decreased the intracellular concentrations of the two enantiomers. This effect disappeared in the presence of a CYP3A4 inducer dexametha- sone. These results indicated that CYP3A4 could influence P-gp efflux, transport and uptake of CLA enantiomers as CYP3A4 substrates and that a duel inhibition to CYP3A4/ P-glycoprotein could enhance their absorption and bioavailability, which provides new insight into the efflux-metabolism alliance and will benefit the clinical pharma- cology of （？） CLA as a candidate drug for treatment of Alzheimer＇ s disease.展开更多
Synthesis of the optically active metabolite of clausenamide CM2 (3, 5-dihydroxy- 5-(a-hydroxylbenzyl)-1-methyl-4-benzylpyrrolidin-2-one) from 3-O-acetyl- clausenamide was described.
CM1, (-)CM1 as well as (±)CM1–the metabolites of clausenamide were synthesized from b-phenyl-(N-p-methoxylbenzyl)-ethanol amine through 8 and 6 steps respec- tively.
Aim To study the excretion of(-)-clausenamide in rats.Methods The urine,feces and bile were collected at predetermined time points after(-)-clausenamide was orally administrated to 6 rats(30 mg·kg^-1).The concent...Aim To study the excretion of(-)-clausenamide in rats.Methods The urine,feces and bile were collected at predetermined time points after(-)-clausenamide was orally administrated to 6 rats(30 mg·kg^-1).The concentrations of(-)-clausenamide and its metabolite 6-OH-(-)-clausnamide were determined by HPLC-MS/MS method using glipzide as the internal reference,and the accumulative excretion amount of(-)-clausenamide and 6-OH-(-)-clausenamide was calculated in the urine,feces and bile,separately.Results(-)-Clausenamide was recovered mostly(44%) from feces in 112 hours,7.1% was found from urine in 120 hours and 0.013% was detected from bile in 24 hours.The accumulative excretions of 6-OH-(-)-clausenamide were 0.92%,0.46% and 0.0003% of the administered dose from feces,urine and bile,respectively.Conclusion The major amount of(-)-clausenamide was recovered from feces after(-)-clausenamide was orally administrated to rats(30 mg·kg^-1).展开更多
文摘A method of high performance liquid chromatographic separation of clausenamide enantiomers with chiral-AGP（α_1-acid glycoprotein） stationary phases has been established.The absolute configurations of（-）clausenamide and（＋）clausenamide are 3S, 4R,5R,6S and 3R,4S,5S,6R,respectively.The present method has been used to analyze the（-）clausenamide and（＋）clausenamide and its analogues such as the major metabolite and synthetic derivatives of clausenamide.
文摘Aim The present study developed a CYP3A4-expressed Caco-2 monolayer model at which effects of the efflux-metabolism alliance on the transport and uptake of clausenamide（CLA） enantiomers as CYP3A4 substrates were investigated. The apparent permeability coefficients （Papp） of （ - ） and （ ＋ ）CLA were higher in the ab- sorptive direction than those in the secretory direction with efflux ratios（ER） of 0. 709 ± 0.411 and 0. 867± 0. 250 （ Х10^-6 -1 cm · s ）, respectively. Their bidirectional transports were significantly reduced by （75.6 ± 87.5）% af- ter treatment with verapamil （ a P-glycoprotein inhibitor） that increased the rate of metabolism by CYP3 A4, whereas the CYP3A4 inhibitor ketoconazole treatment markedly enhanced the basolateral to apical flux of （ - ） and （ ＋ ） CLA with ERs being 2. 934 ± 1. 432 and 1. 877 ± 0. 148 （ Х 10^-6 cm/s） respectively. These changes could be blocked by the duel CYP3A4/P-glycoprotein inhibitor cyclosporine A, consequently, Papp values for CLA enanti- omers in both directions were significantly greater than those obtained by using verapamil or ketoconazole, and their ERs were similar to those following （ - ） or （ ＋ ）-isomer treatment alone. Furthermore, the uptake of （ - ）CLA was more than that of （ ＋ ）CLA in the transfected cells. Incubation with ketoeonazole decreased the intracellular concentrations of the two enantiomers. This effect disappeared in the presence of a CYP3A4 inducer dexametha- sone. These results indicated that CYP3A4 could influence P-gp efflux, transport and uptake of CLA enantiomers as CYP3A4 substrates and that a duel inhibition to CYP3A4/ P-glycoprotein could enhance their absorption and bioavailability, which provides new insight into the efflux-metabolism alliance and will benefit the clinical pharma- cology of （？） CLA as a candidate drug for treatment of Alzheimer＇ s disease.
基金This work was supported by the National Natural Science Foundation of China. ( No.29790121)
文摘Synthesis of the optically active metabolite of clausenamide CM2 (3, 5-dihydroxy- 5-(a-hydroxylbenzyl)-1-methyl-4-benzylpyrrolidin-2-one) from 3-O-acetyl- clausenamide was described.
基金This work was supporcd by the National Natural Science Foundation of China(No.29790121)
文摘CM1, (-)CM1 as well as (±)CM1–the metabolites of clausenamide were synthesized from b-phenyl-(N-p-methoxylbenzyl)-ethanol amine through 8 and 6 steps respec- tively.
文摘Aim To study the excretion of(-)-clausenamide in rats.Methods The urine,feces and bile were collected at predetermined time points after(-)-clausenamide was orally administrated to 6 rats(30 mg·kg^-1).The concentrations of(-)-clausenamide and its metabolite 6-OH-(-)-clausnamide were determined by HPLC-MS/MS method using glipzide as the internal reference,and the accumulative excretion amount of(-)-clausenamide and 6-OH-(-)-clausenamide was calculated in the urine,feces and bile,separately.Results(-)-Clausenamide was recovered mostly(44%) from feces in 112 hours,7.1% was found from urine in 120 hours and 0.013% was detected from bile in 24 hours.The accumulative excretions of 6-OH-(-)-clausenamide were 0.92%,0.46% and 0.0003% of the administered dose from feces,urine and bile,respectively.Conclusion The major amount of(-)-clausenamide was recovered from feces after(-)-clausenamide was orally administrated to rats(30 mg·kg^-1).
