Pharmacokinetics of Paclitaxel in Rabbits with Carbon Tetrachloride-Induced Hepatic Failure

Choi, Jun-Shik The Pharmaceutical Society of Korea 2002 Archives of Pharmacal Research Vol.25 No.6

The pharmacokinetic of paclitaxel (1 mg/kg, i.v.) was investigated in rabbits with carbon tetrachloride-induced hepatic failure. The area under the plasma concentration-time curve (AUC) of paclitaxel was significantly (p<0.01) increased in severe carbon tetrachloride-induced hepatic failure rabbits ($1364.54{\pm}382.07$ ng/ml$\cdot$hr) compared to that of normal rabbits ($567.52{\pm}141.88$ ng/ml$\cdot$hr), but not significantly in moderate carbon tetrachloride-induced hepatic failure rabbits ($803.1{\pm}208.81$ ng/ml$\cdot$hr). The volume of distribution (Vd) (6.25$\pm$1.56 L) and the elimination rate constant($\beta$) ($0.09{\pm}0.025{\;}hr^{-1}$) of paclitaxel in severe carbon tetrachloride-induced hepatic failure rabbits were significantly (p<0.05) decreased compared to those of normal rabbits ($11.65<{\pm}2.91$L, $0.12{\pm}0.030{\;}hr^{-1}$), but not significantly in moderate carbon tetrachloride-induced hepatic failure rabbits ($9.46{\pm}2.37$ L, $0.10{\pm}0.026{\;}hr^{-1}$). Total body clearance ($CL_t$) of paclitaxel in severe carbon tetrachloride-induced hepatic failure rabbits ($0.733{\pm}0.183$ L/hr/kg) was significantly (p<0.01) decreased compared to that of normal rabbits ($1.762{\pm}0.440$ L/hr/kg), but not significantly in moderate carbon tetrachloride-induced hepatic failure rabbits ($1.245{\pm}0.311$ L/hr/kg). The half-life(t1/2) of paclitaxel in severe carbon tetrachloride-induced hepatic failure rabbits ($7.71{\pm}2.16$ hr) was significantly (p<0.05) increased compared to that of normal rabbits ($5.75{\pm}1.44$hr), but not significantly in moderate carbon tetrachloride-induced hepatic failure rabbits ($6.77{\pm}1.76$hr). This results could be due to inhibition of paclitaxel metabolism in liver disorder rabbits since paclitaxel is essentially metabolized in liver. The findings suggest that the dosage regimen of paclitaxel should be adjusted when the drug would be administered in patients with liver disorder in a clinical situation.

Pharmacokinetics of Paclitaxel in Rabbits with Carbon Tetrachloride-Induced Hepatic Failure

Jun-ShikChoi 대한약학회 2002 Archives of Pharmacal Research Vol.25 No.6

The pharmacokinetic of paclitaxel (1 mg/kg, i.v.) was investigated in rabbits with carbon tetrachloride- induced hepatic failure. The area under the plasma concentration-time curve (AUC) of paclitaxel was significantly (p<0.01) increased in severe carbon tetrachloride-induced hepatic failure rabbits (1364.54 ± 382.07 ng/ml . hr) compared to that of normal rabbits (567.52 ± 141.88 ng/ml . hr), but not significantly in moderate carbon tetrachloride-induced hepatic failure rabbits (803.1 ± 208.81 ng/ml . hr). The volume of distribution (Vd) (6.25 ± 1.56 L) and the elimination rate constant(b) (0.09 ± 0.025 hr-1) of paclitaxel in severe carbon tetrachloride-induced hepatic failure rabbits were significantly (p<0.05) decreased compared to those of normal rabbits (11.65 ± 2.91 L, 0.12 ± 0.030 hr-1), but not significantly in moderate carbon tetrachlorideinduced hepatic failure rabbits (9.46 ± 2.37 L, 0.10 ± 0.026 hr-1). Total body clearance (CLt) of paclitaxel in severe carbon tetrachloride-induced hepatic failure rabbits (0.733 ± 0.183 L/hr/kg) was significantly (p<0.01) decreased compared to that of normal rabbits (1.762 ± 0.440 L/hr/kg), but not significantly in moderate carbon tetrachloride-induced hepatic failure rabbits (1.245 ± 0.311 L/hr/kg). The half-life(t1/2) of paclitaxel in severe carbon tetrachloride-induced hepatic failure rabbits (7.71 ± 2.16 hr) was significantly (p<0.05) increased compared to that of normal rabbits (5.75 ± 1.44 hr), but not significantly in moderate carbon tetrachloride-induced hepatic failure rabbits (6.77 ± 1.76 hr). This results could be due to inhibition of paclitaxel metabolism in liver disorder rabbits since paclitaxel is essentially metabolized in liver. The findings suggest that the dosage regimen of paclitaxel should be adjusted when the drug would be administered in patients with liver disorder in a clinical situation.

사염화탄소(四鹽化炭素)를 투여(投輿)한 MICE 혈청(血淸)내 효소(酵素) 활성(活性) 및 생화학적(生化學的) 조성(造成)의 변화(變化)

김순태 ( Soon Tae Kim ),손재권 ( Jae Kweon Son ),김상윤 ( Sang Yun Kim ) 한국가축위생학회 1993 韓國家畜衛生學會誌 Vol.16 No.2

Carbon tetrachloride (CCl4) has been used to treat a variety of parasitic infection in both large and small animals, including Fasciola hepatica. Recently, we can easily contest with carbon tetrachloride in air, food, water, rain and industry area etc. and it is using in order to induce liver injury in laboratory. In this study, we investigated activitis of LDH, ALP, AST and ALT and amount of cholesterol, triacylglycerol, glucose and BUN in mice serum exposed to CCl4. The mice divided into a Naive control(A), corn oil control(B) and experimental group(C, D). Naive control group(A) was given feed and water only. Corn oil control group(B) was given corn oil lml/100g of body weight(B.W). Experimental group(C) was given carbon tetrachloride 1ml/l00g B.W.(CCl4:corn oil=1:20(V/V)). Experimental group(D) was given carbon teterachloride 1ml/100g B.W.(CC14:corn oil=1:10(V/V)). The results obtained were summarized as follows: 1) The body weight was declined after the 10th day in mice exposed to carbon tetrachloride. 2) The total protein level in serum was significantly in mice exposed to carbon tetrachloride(P≤0.05). The albumin and A/G ratio was decresed significantly in mice exposed to carbon tetrachloride (P≤0.01). 3) All of the activity of LDH, AST, ALT and ALP in mice serum exposed to carbon tetrachloride: incresed significantly activity of LDH(P≤0.05), incresed significantly activity of AST(P≤0.05, P≤0.01), incresed significantly activity of ALT and ALP(P≤0.05, P≤0.01). 4) The amount of cholesterol and triacylglycerol, lipid metabolite products in serum was incresed in case of cholesterol but did not change in case of triacylglycerol.

마늘에 의한 사염화탄소 간독성의 보호 효과

이종문,박정덕,홍연표,최병선,Lee, Jong-Moon,Park, Jung-Duck,Hong, Yeon-Pyo,Choi, Byung-Sun 대한예방의학회 2002 예방의학회지 Vol.35 No.3

Objectives : The purpose of this study was to find the protective effects of garlic on the halogenated hydrocarbon induced hepatotoxicities, and the possible protection mechanisms involved. Methods : Male Sprague-Dawley rats received garlic (0.5%) or regular diet, for 4 weeks. This was followed by a single dose of corn oil (the controls), carbon tetrachloride (400mg/kg body weight) and trichloroethylene (2,000mg/kg body weight) being administered to each diet group. Blood samples were collected 24 hours fellowing the administration, and the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALD activities measured. The liver samples were studied for their cytochrome P450 and CYP2E1 contents, lipid peroxidation and histopathology. Results : rho results for the group receiving the 9.5% garlic diet showed a slight decrease of CYP2E1 expression compared with the regular diet group. Carbon tetrachloride was significantly decreased the CYP2E1 contents in both the regular and garlic diet groups, but the trichloroethylene remained unchanged. Garlic did not decrease the lipid peroxidation of the liver in the control group, but attenuated the increase of lipid peroxidation caused by carbon tetrachloride. Garlic attenuated the increase of both the serum AST and ALT activities caused by carbon tetrachloride. The histopathelogical observations also showed that garlic attenuated centrilobular necrosis and vacuolar degenerative changes significantly in the carbon tetrachloride treated group. Conclusions : The results indicate that garlic attenuates the carbon tetrachloride-induced hepatotoxicity, through the prevention of the metabolic activation and lipid peroxidation.

Effect of Relative Humidity on the Adsorption Characteristics of Carbon Tetrachloride in a Fixed Bed

Kim, Tae Young,Kim, Seung Jai,Cho, Sung Yong 한국공업화학회 2004 Journal of Industrial and Engineering Chemistry Vol.10 No.2

Activated carbon is used as an adsorbent in various industrial fields, such as for solvent recovery, gas separation, and deodorization. In this study, the effect of relative humidity on the adsorption characteristics of carbon tetrachloride by a pellet-type carbon adsorbent was investigated. An isothermal adsorption column was set-up to study the effects of feed concentration, flow rate, and relative humidity on the adsorption of carbon tetrachloride onto activated carbon. The relative humidity of the air stream was controlled in a range from 0 to 80% (W/W). Adsorption equilibrium isotherms of carbon tetrachloride with relative humidity were measured by the column dynamic method at 298.15 K. Adsorption isotherms of carbon tetrachloride, with or in the absence of relative humidity, onto activated carbon are expressed well by a Langmuir isotherm. The adsorption capacity of carbon tetrachloride decreased with increasing relative humidity. An adsorption model based on the linear driving force approximation (LDFA) was found to be applicable to fit the experimental data.

일차 배양한 흰쥐의 간세포에서 사염화탄소로 인한 독성에 미치는 비테인의 효과

김선여(Sun Yeou Kim),김홍표(Hong Pyo Kim),이미경(Mi Kyeong Lee),김승희(Seung Hee Kim),문애리(A Ree Moon),한형미(Hyung Mi Han),허훈(Hoon Huh),김영중(Young Choong Kim) 대한약학회 1993 약학회지 Vol.37 No.5

Betaine, a major component of Lycii Fructus, was evaluated for its anti-hepatotoxic activity on carbon tetrachloride-induced hepatotoxicity in primary cultured rat hepatocytes. Betaine was found to attenuate carbon tetrachloride-induced hepatotoxicity both morphologically and biochemically. Typical hepatocyte necrosis due to carbon tetrachloride seemed to be reduced by 50 to 500mcM of betaine under microscopical observation. The value of glutamic pyruvic transaminase released from the hepatocytes into the medium significantly decreased as betaine concentration increased. Betaine also significantly elevated the reduced activities of some enzymes, cytochrome P-450, 7-ethoxycoumarin-O-deethylase and glutathione-S-transferase, involved in xenobiotic metabolism due to carbon tetrachloride-induced hepatotoxicity. These results demonstrate a possible hepato-protective role of betaine against fatty liver that could be easily induced by carbon tetrachloride.

Pharmacokinetics of Acebutolol and Its Main Metabolite, Diacetolol After Oral Administration of Acebutolol in Rabbits with Carbon Tetrachloride-Induced Hepatic Failure

JunShikChoi,범진필 대한약학회 2002 Archives of Pharmacal Research Vol.25 No.4

Pharmacokinetic characteristics of acebutolol and its main metabolite, diacetolol, following a single 10 mg/kg oral dose, were investigated in rabbits with carbon tetrachloride-induced hepatic failure. Plasma concentrations of acebutolol and diacetolol were determined by a high performance liquid chromatography assay. The area under the plasma concentration-time curves (AUC) and maximum plasma concentration (Cmax) of acebutolol were significantly increased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. The ratio of the diacetolol to total acebutolol in plasma (i.e., metabolite percentage rate) was significantly decreased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. Volume of distribution (Vd) and total body clearance (CLt) of acebutolol were significantly decreased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. Slope of terminal phase (b) of acebutolol was significantly decreased in hepatic failure rabbits. These findings suggest that the Vd, CLt and b of acebutolol were significantly decreased as a result of inhibition of the hepatic metabolism in moderate to severe hepatic failure rabbits. Therefore, dose adjustment may be necessary for acebutolol in hypertensive patients with hepatic damage.

Pharmacokinetics of Acebutolol and Its Main Metabolite, Diacetolol After Oral Administration of Acebutolol in Rabbits with Carbon Tetrachloride-Induced Hepatic Failure

Choi, Jun-Shik,Burm, Jin-Pil The Pharmaceutical Society of Korea 2002 Archives of Pharmacal Research Vol.25 No.4

Pharmacokinetic characteristics of Acebutolol and its main metabolite, diacetolol, following a single 10 mg/kg oral dose, were investigated in rabbits with carbon tetrachloride-induced hepatic failure. Plasma concentrations of acebutolol and diacetolol were determined by a high performance liquid chromatography assay. The area under the plasma concentration-time curves (AUC) and maximum plasma concentration ($C_{max}$) of acebutolol were significantly increased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. The ratio of the diacetolol to total acebutolol in plasma (i.e., metabolite percentage rate) was significantly decreased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. Volume of distribution ($V_{d}$) and total body clearance ($CL_{t}$) of acebutolol were significantly decreased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. Slope of terminal phase ($\beta$) of acebutolol was significantly decreased in hepatic failure rabbits. These findings suggest that the $V_{d},{\;}CL_{t}$ and $\beta$ of acebutolol were significantly decreased as a result of inhibition of the hepatic metabolism in moderate to severe hepatic failure rabbits. Therefore, dose adjustment may be necessary for acebutolol in hypertensive patients with hepatic damage.

사염화탄소의 장기(長期) 투여(投與)로 유발된 백서(白鼠) 간경변(肝硬變)에 대한 형방지황탕(荊防地黃湯)의 조직병리학적 영향

김승모,Kim, Seong-Mo 대한한방내과학회 2008 大韓韓方內科學會誌 Vol.29 No.2

Objective : This study was carried out to investigate the effects of oral administration of Hyeungbangjihwang-tang (HBJHT) on the liver cirrhosis of rats induced by Carbon tetrachloride for 10 weeks. Method : The histopathological changes were observed. The HBJHT extracts were daily dosed at 50, 100 and 200mg/kg for 12 weeks. Results : Severe hepatocellular necrosis and ballooning, hyperplasia of connective tissue, subdued reduction of hepatic lobule, and hyperplasia of bile duct in portal triad were dramatically decreased in the HBJHT-treated group compared to that of the Carbon tetrachloride-treated control group in histopathological observation. The diameter of hepatic lobules was significantly enlarged in the HBJHT-treated group compared to that of the Carbon tetrachloride-treated control group, and the amounts of connective tissue, degenerative cells and bile ducts were significantly and dose-dependently decreased. Conclusion : It is concluded that HBJHT has a significant recovering effect on the liver of rats induced by carbon tetrachloride.

흰쥐에 있어서 톨루엔 대사에 미치는 간손상의 영향

차상은,윤종국,이상일,Cha, Sang-Eun,Yoon, Chong-Guk,Lee, Sang-Il 한국독성학회 1998 Toxicological Research Vol.14 No.3

This study was performed to evaluate the effect of liver damage on toluene metabolism in rats pretreated with carbon tetachloride. Liver damage in rats was induced by administration of 0.1ml of carbon tetrachloride per 100g of body wight intraperitoneally every day for four weeks except the last day before sacrifice. One day before sacrifice, toluene was administered to the animals instead of carbon tetrachloride. Rats were sacrificed at the 1st, the 2nd, the 3rd and the 4th week after the first administration of carbon tetachloride. Based on the histopathological findings, liver weight and serum alanine aminotransferase, the $CCl_4$-preteated group was found to have gradual severe liver damage. Especially the degree of liver injury became increasingly severe throughout the whole course of the experiment. The contnts of hippuric acid in urine lower in the all groups pretreated with $CCl_4$than that of the control. The contents of hepatic cytochrome P450(CYP), benzylalcohol dehydrogenase and benzaldehyde dehydrogenase activities were decreased in $CCl_4$-pretreated rats than those of the control. The $CCl_4$treated animals showed the gradual decreased activities of these enzyme as injection times elapsed. Km values of the benzylalcohol dehydrogenase in pooled liver samples from $CCl_4$-pretreated or control groups were similar. On the other hand, Vmax values of the $CCl_4$-pretreated group was lower than of the control. Therefore, it can be concluded that reduction of the toluene metabolism in damaged rat liver induced with $CCl_4$was due to the inhibition of CYP content, bezylalcohol and benzaldehyde dehydrogenase activities which related with toluene metabolic enzyme system.