• Archives of Pharmacal Research
• /
• 제22권1호
• /
• pp.60-67
• /
• 1999

The object of this work was to study the pharmacokinetic differences and the cause of these differences in cirrhotic rats induced by biliary obstruction when aminophylline (8 mg/kg as theophylline, i.v.) was administered. The concentrations of theophylline and its major metabolite (1,3-dimethyluric acid) in plasma were determined by HPLC. In addition, formation of 1,3-dimethyluric acid from theophylline in microsomes and the changes in the activity of drug metabolizing enzymes, which are suggested to be involved in theophylline metabolism, were determined. In cirrhotic rats, the systemic clearance of theophylline was reduced to 30% of the control value while AUC (area under the palsma concentration-tie curve) and (t1/2)$\beta$ were increased 1.3 fold and3.5 fold, respectively. The formation of 1,3-dimethyluric acid was decreased to 30% of the control value in microsomes of cirrhotic rat liver. In cirrhotic rat liver, activities of aniline hydroxylase (CYP2E1 related), erythromycin-N-demethylase (CYP3A related), and methoxyresorufin-O-demethylase (CYP1A2 related), which were reported to be related with theophyline metabolism, were decreased to 67%, 53%, and 76% that of normal rat liver, respectively. From the results, it can be concluded that in cirrhotic rats induced by biliary obstruction, the total body clearance of theophylline is markedly reduced and it may be due to decreased activity of drug metabolizing enzymes in liver.

• 한국응용약물학회:학술대회논문집
• /
• 한국응용약물학회 1993년도 제2회 신약개발 연구발표회 초록집
• /
• pp.71-71
• /
• 1993

Carboxylesterase is widely distributed in the tissues of vertebrates, insects, plants and mycobacteria. Among various tissues of animals and humans, the highest esterase activity with various substrates is found in the liver. Kidney has moderate carboxylesterase activity in the proximal tubules. Considerable esterase activity is also found in the small intestine epithet elial cells and serum of mammals. Besides these tissues, carboxylesterase has been found in the lung, testis, adipose tissue, nasal mucosa and even in the central nervous system. Hepatic microsomal carboxylesterase catalyzes the hydrolysis of a wide variety of endogenous and exogenous compounds such as carboxylester, thioester and aromatic amide. Since carboxylesterases are important for metabolic activation of prodrugs and detoxification of xenobiotics, differences in substrate specificity and immunological properties of this enzyme are important in connection with choosing a suitable laboratory animal for the evaluation of biotransformation and toxicity of drugs. On the other hand, liver, kidney, intestine and serum were found to contain multiple forms of carboxylesterases in animal species and humans. In fact, we have purified more than fifteen isoforms of carboxylesterases from microsomes of liver, kidney and intestinal mucosa of nine animal species and humans. and characteristics of these isoforms were compared each other in terms of their physical and immunochemical properties. On the other hand, we have reported that hepatic microsomal carboxylesterases are induced by many exogenous compounds such as phenobarbital, polycyclic aromatic hydrocarbons, Aroclor 1254, aminopyrine and clofibrate. Later, we showed that some isoforms of hepatic carboxylesterase were induced by glucocorticoids such as dexamethasone and 16 ${\alpha}$-carbonitrile, but other isoforms were rather inhibited by these compounds. These findings indicate that involvement of carboxylesterases in the metabolism and toxicity of drugs should be explained by the isoforms involved. Since 1991, we have carried out detailed research investigating the types of carboxylesterases involved in the metabolic activation of CPT-11, a derivative of camptothecin, to the active metabolite, SN-38. The results obtained strongly suggest that some isoforms of carboxylesterase of liver microsomes and intestinal mucosal membrane are exclusively involved in CPT-11 metabolism. In this symposium, the properties of carboxylesterase isoforms purified from liver, kidney and intestine of animal species and humans are outlined. In addition, metabolism of CPT-11, a novel antitumor agent, by carboxylesterases in relation to the effectiveness will also be discussed.

• 한국독성학회:학술대회논문집
• /
• 한국독성학회 2001년도 International Symposium on Dietary and Medicinal Antimutgens and Anticarcinogens
• /
• pp.196-196
• /
• 2001

Stereoselective metabolism and inhibitory potential of lansoprazole enantiomers were evaluated from the incubational studies of human liver microsomes and eDNA-expressed CYP isoforms in vitro. The formation of lansoprazole sulfone from both enantiomers appeared to be catalyzed by single and low affinity enzyme. Lansoprazole 5-hydroxylation, however, appeared to be mediated by two kinetically distinct CYP enzymes.(omitted)

• Archives of Pharmacal Research
• /
• 제18권6호
• /
• pp.381-384
• /
• 1995

Covalent binding of the reactive metabolites of SC_42867 to microsomal proteins has been examined. In the absence of inhibitor of cytochrome oxydase (.alpha.-naphtyl-isothiocyanate) or a radical scavenger (3-terthiobuty-4-hydroxyanisol), up to 4.0% of total redioactivity used in the assay could irreversibly bind to proteins. In the presence of an inhibitor, the highest percentage of covalent binding observed is 0.7% a significant decrease of the metabolism of SC42876 was observed. These results suggest in a cytochrome P-450 dependent generation of SC_42867 metabolites significantly take part in the covalent binding process.

• 대한약학회:학술대회논문집
• /
• 대한약학회 2000년도 춘계총회 및 학술대회
• /
• pp.219.1-219.1
• /
• 2000

• 대한약학회:학술대회논문집
• /
• 대한약학회 2000년도 NEW STRATEGY FOR DRUG DEVELOPMENT IN POST-GENOMIC ERA(대한약학회)
• /
• pp.271.1-271.1
• /
• 2000

• Toxicological Research
• /
• 제32권3호
• /
• pp.207-213
• /
• 2016

Although propolis is one of the most popular functional foods for human health, there have been no comprehensive studies of herb-drug interactions through cytochrome P450 (CYP) inhibition. The purpose of this study was to determine the inhibitory effects of propolis on the activities of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 using pooled human liver microsomes (HLMs). Propolis inhibited CYP1A2, CYP2E1 and CYP2C19 with an $IC_{50}$ value of 6.9, 16.8, and $43.1{\mu}g/mL$, respectively, whereas CYP2A6, 2B6, 2C9, 2D6, and 3A4 were unaffected. Based on half-maximal inhibitory concentration shifts between microsomes incubated with and without nicotinamide adenine dinucleotide phosphate, propolis-induced CYP1A2, CYP2C19, and CYP2E1 inhibition was metabolism-independent. To evaluate the interaction potential between propolis and therapeutic drugs, the effects of propolis on metabolism of duloxetine, a serotonin-norepinephrine reuptake inhibitor, were determined in HLMs. CYP1A2 and CYP2D6 are involved in hydroxylation of duloxetine to 4-hydroxy duloxetine, the major metabolite, which was decreased following propolis addition in HLMs. These results raise the possibility of interactions between propolis and therapeutic drugs metabolized by CYP1A2.

• Mass Spectrometry Letters
• /
• 제9권1호
• /
• pp.24-29
• /
• 2018

DC23, a triazolothione resorcinol analogue, is known to inhibit heat shock protein 90 and pyruvate dehydrogenase kinase which are up-regulated in cancer and diabetes, respectively. This study was performed to elucidate the metabolism of DC23 in human liver microsomes (HLMs). HLMs incubated with DC23 in the presence of uridine 5'-diphosphoglucuronic acid (UDPGA) and/or ${\beta}$-nicotinamide adenine dinucleotide phosphate (NADPH) resulted in the formation of four metabolites, M1-M4. M1 was identified as DC23-N-Oxide, on the basis of LC-MS/MS analysis. DC23 was further metabolized to its glucuronide conjugates (M2, M3, and M4). In vitro metabolic stability studies conducted with DC23 in HLMs revealed significant glucuronide conjugation with a $t_{1/2}$ value of 1.3 min. The inhibitory potency of DC23 on five human cytochrome P450s was also investigated in HLMs. In these experiments, DC23 inhibited CYP2C9-mediated tolbutamide hydroxylase activity with an $IC_{50}$ value of $8.7{\mu}M$, which could have implications for drug interactions.

• 한국수산과학회지
• /
• 제33권2호
• /
• pp.87-92
• /
• 2000

간장중의 활성산소 및 제거효소의 활성에 미치는 영향을 평가하기 위하여 미역의 건조분말을 $10{\%},\;20{\%},\;40{\%}$-첨가 조제한 미역국수 ($10{\%},\;20{\%},\;40{\%}\;FBA-noodle$)를 4주동안 SD계 흰쥐에 투여하여 미역국수의 생리작용을 평가하였다. $10{\%},\;20{\%},\;40{\%}$ FBA-noodle의 투여그룹의 mitochondria의 ${\cdot}OH$ 생성은 대조그룹 대비 각각 $20{\%},\;25{\%},\;35{\%}$의 현저한 OH 생성 억제효과가 인정되었다. 또한 $10{\%},\;20{\%},\;40{\%}$ FBA-noodle의 투여그룹의 microsome의 ${\cdot}OH$ 생성도 대조그룹 대비 $12{\~}20{\%}$의 유의적인 ${\cdot}OH$ 생성 억제효과가 인정되었다. $10{\%},\;20{\%},\;40{\%}$ FBA-noodle의 microsome의 $H_2O_2$의 생성은 유의적인 억제효과를 인정할 수 없었지만, cytosol중의 $O_2^({\cdot}-)$ 생성은 $20{\%},\;40{\%}$ FBA-noodle에서 $10{\%}$의 $O_2^({\cdot}-)$의 생성 억제효과가 인정되었다. $10{\%},\;20{\%},\;40{\%}$ FBA-noodle 투여그룹의 간장 mitochondria의 Mn-SOD 활성은 대조그룹 대비 $10{\~}15{\%}$의 Mn-SOD 활성의 증가효과가 인정되었다. 간장 microsome의 Mn-SOD 활성은 $10{\%} 및 20{\%}$ FBA-noodle 투여그룹은 Mn-SOD 활성의 유의적인 증가 효과를 인정할 수 없었지만, $40{\%}$ FBA-noodle 투여그룹은 $12{\%}$의 유의적인 Mn-SOD 활성 증가효과가 인정되었다. 또한 $10{\%},\;20{\%},\;40{\%}$ FBA-noodle의 투여그룹의 간장 cytosol의 Cu, Zn-SOD 활성은 대조그룹 대비 $10{\~}20{\%}$의 Cu, Zn-SOD 활성의 유의적인 증가효과가 인정되었다. 한편 간장 cytosol의 글루타치온 퍼옥시다아제 (GSHPx) 활성을 평가하여 보면 $10{\%}, 20{\%}, 40{\%}$ FBA-noodle 투여그룹의 cytosol의 GSHPx 활성은 대조그룹 대비 $20{\~}40{\%}$의 매우 효과적인 GSHPx활성의 증가효과가 인정되었다. $10{\%}, 20{\%}, 40{\%}$ FBA-noodle 투여그룹의 mitochondria의 LPO의 함량을 비교하여 보면 $10{\%}$ FBA-noodle은 유의적인 LPO의 생성 억제효과를 인정할 수 없었지만, $20{\%},\;40{\%}$ FBA-noodle은 $10{\%}$의 유의적인 LPO 생성 억제효과가 인정되었다. $10{\%},\;20{\%},\;40{\%}$ FBA-noodle 투여그룹의 microsome의 LPO의 함량은 $10{\%}$ FBA-noodle은 유의적인 LPO의 생성 억제효과를 인정할 수 없었지만, $20{\%} 및 40{\%}$ FBA-noodle은 약 $10{\~}12{\%}$의 유의적인 LPO 생성 억제효과가 인정되었다.

• 한국임상약학회지
• /
• 제9권1호
• /
• pp.55-61
• /
• 1999

The object of this work was to study the pharmacokinetic differences and the cause of these differences in cirrhotic rats induced by N,N-dimethylnitrosamine or carbon tetrachloride treatment when aminophylline (8 mg/kg as theophylline, i.v.) was injected. The concentrations of theophylline and its major metabolite (1,3-dimethyluric acid) in plasma were determined by HPLC. In addition, formation of 1,3-dimethyluric acid from theophylline in microsomes was determined. In cirrhotic rats, the systemic clearance of theophylline was reduced to $17\%$ of the control value while AUC (area under the plasma concentration-time curve) and $(t_{1/2})_{\beta}$ were increased to about 6 fold and 10 fold, respectively. The formation of 1,3-dimethyluric acid was decreased to $33-41\%$ of the control value in microsomes of cirrhotic rat liver. From these results, it can be concluded that in cirrhotic rats induced by N,N-dimethylnitrosamine or carbon tetrachloride the total body clearance of theophylline is markedly reduced due to a reduced hepatic metabolism.