Effects of cysteine on the pharmacokinetics of intravenous chlorzoxazone in rats with protein–calorie malnutrition

Kim, Yoon G.; Cho, Min K.; Kwon, Jong Won; Kim, Sang G.; Chung, Suk Jae; Shim, Chang-Su; Lee, Myung G.

doi:10.1002/bdd.300.abs

Cited by 6 publications

(11 citation statements)

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“…After intravenous administration of adriamycin, primarily metabolized by CYP3A in rats [8], the 24-h urinary excretion of M3, an aglycone metabolite of adriamycin, decreased in rats with PCM [9]. However, by cysteine supplementation (rats with PCMC), the 24-h urinary excretion of M3 increased significantly as compared to that in rats with PCM [9]. Above data indicated that cysteine was efficient in restoring CYP450 expression and metabolic activities.…”

Section: Introductionmentioning

confidence: 43%

“…Interestingly, cysteine supplementation (rats with PCMC) significantly reduced the plasma concentrations of the diuretic and concomitantly restored Cl nr toward control [5,7]. After intravenous administration of adriamycin, primarily metabolized by CYP3A in rats [8], the 24-h urinary excretion of M3, an aglycone metabolite of adriamycin, decreased in rats with PCM [9]. However, by cysteine supplementation (rats with PCMC), the 24-h urinary excretion of M3 increased significantly as compared to that in rats with PCM [9].…”

Section: Introductionmentioning

confidence: 99%

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Effects of cysteine on the pharmacokinetics of intravenous chlorzoxazone in rats with protein–calorie malnutrition

Kim

Cho

Kwon

et al. 2002

Biopharm & Drug Disp

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The effects of cysteine on the pharmacokinetics of chlorzoxazone (CZX) and one of its metabolites, 6-hydroxychlorzoxazone (OH-CZX), were investigated after intravenous administration of CZX, 25 mg/kg, to control rats (4-week fed on 23% casein diet) and rats with PCM (4-week fed on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily during the fourth week). In rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of OH-CZX (436 compared with 972 microgmin/ml) and the percentages of intravenous dose of CZX excreted in 8-h urine as OH-CZX (20.2 compared with 38.5%) were significantly smaller than those in control rats. The above data indicated that the formation of OH-CZX from CZX decreased significantly in rats with PCM due to a significant decrease in chlorzoxazone-6-hydroxylase activity (328 compared with 895 pmol/min/mg protein) in the rats. The results were expected since in rats with PCM, hepatic CYP2E1 expression and its mRNA levels decreased significantly as compared to control, and CZX was metabolized to OH-CZX primarily by CYP2E1 in rats. By cysteine supplementation (rats with PCMC), some pharmacokinetic parameters restored fully (hepatic microsomal chlorzoxazone 6-hydroxylation activity based on both mg protein and nmol CYP450) or partially (total body clearance and apparent volume of distribution at steady state of CZX, and AUC, terminal half-life and 8-h urinary excretion of OH-CZX) to control levels.

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Section: Introductionmentioning

confidence: 43%

Section: Introductionmentioning

confidence: 99%

Effects of cysteine on the pharmacokinetics of intravenous chlorzoxazone in rats with protein–calorie malnutrition

Kim

Cho

Kwon

et al. 2002

Biopharm & Drug Disp

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“…Interestingly, the altered cytochrome P450 expression by PCM completely or partially returned to the level of control by oral cysteine supplementation for one week (250 mg/kg, twice daily during the fourth week, PCMC). Hence, in rats with PCMC, some pharmacokinetic parameters of drugs which were mainly metabolized by CYP1A (azosemide), CYP3A (adriamycin) or CYP2E1 (chlorzoxazone) were retuned to control [4][5][6]. The effects of cysteine to counteract changes in some pharmacokinetics of drugs due to PCM was proven for azosemide [4], adriamycin [5] and chlorozoxazone [6].…”

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confidence: 99%

Effects of cysteine on the pharmacokinetics of itraconazole in rats with protein‐calorie malnutrition

Lee

Ahn

Kim

et al. 2003

Biopharm & Drug Disp

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The effects of cysteine on the pharmacokinetics of itraconazole were investigated after intravenous, 20 mg/kg, and oral, 50 mg/kg, administration of the drug to control rats (fed for 4 weeks on 23% casein diet) and rats with PCM (protein-calorie malnutrition, fed for 4 weeks on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily during the fourth week). After intravenous administration of itraconazole to rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of itraconazole was significantly greater (3580 compared with 2670 and 2980 microg min/ml) than those in control rats and rats with PCMC (the values between control rats and rats with PCMC were not significantly different). The above data suggested that metabolism of itraconazole decreased significantly in rats with PCM due to suppression of hepatic microsomal cytochrome p450 (CYP) 3A23 in the rats. The results could be expected since in rats with PCM, the level of CYP3A23 decreased significantly as compared to control. Itraconazole was reported to be metabolized via CYP3A4 to several metabolites, including hydroxyitraconazole, in human subjects. Human CYP3A4 and rat CYP3A1 (CYP3A23) proteins have 73% homology. By cysteine supplementation (rats with PCMC), the AUC of itraconazole was restored fully to control levels.

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“…We prepared model rats with various degrees of acute hepatic failure induced by administering various doses of CCl 4 . To examine the degree of CL tot decrease in acute hepatic failure, we selected eight probe drugs which are metabolized by various CYP isoforms: caffeine 25) by CYP1A2, doxorubicin 26) by CYP2B1, tolbutamide 27) by CYP2C11, chlorzoxazone 28) by CYP2E1, and cyclosporine A, 29) lidocaine, 30) tacrolimus 29) and zonisamide 31) by CYP3A2. We found that the blood or plasma concentrations of these drugs in CCl 4 -treated rats were significantly higher than those in control rats (Fig.…”

Section: Discussionmentioning

confidence: 99%

Serum Aminotransferase Activity as a Predictor for Estimation of Total Clearance of Hepatically Metabolized Drugs in Rats with Acute Hepatic Failure

Yokogawa

Ido

Kurihara

et al. 2006

Biological & Pharmaceutical Bulletin

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In treating patients with hepatic failure, it is necessary to set an appropriate drug dosing schedule to take into account of their altered drug disposition kinetics. However, little work has been done to estimate the decrease of total clearance (CL tot ) in relation to the degree of residual hepatic function. Therefore, there is great need for a suitable marker to quantitatively predict the hepatic metabolic capacity in patients with hepatic failure.In humans, there are five predominant families of cytochrome P450 (CYP) species, CYP1A, CYP2C, CYP2D, CYP2E and CYP3A; all of the isoforms differ in their patterns of drug-metabolizing activity, 1) and the amounts of the isoforms in the liver are altered under conditions of hepatic failure.2) The drug-metabolizing activity of the liver may be evaluated on the basis of the correlation between the clearance and the ratio of the metabolite(s) to unchanged drug after the administration of specific inhibitors of various CYP isoforms.Recently, there have been many reports on the expression levels of CYP isoform mRNAs in human liver collected by hepatobiopsy, but no clear correlation has been found between expression levels and the degree of hepatic failure. 3,4) Finnstrom et al. reported that the expression of CYP mRNA in liver is different from that in blood; therefore, blood cannot serve as a surrogate organ for assessment of the expression of the CYP genes in liver.5) Panduro et al. 6) reported that liver regeneration and fibrosis are related to g-carboxylase activity, which is associated with a prolongation of prothrombin time in plasma in rats treated with CCl 4 . Clinically, indocyanine green is commonly used to assess hepatic function. 7)However, none of these procedures appears to be suitable for predicting the decrease in hepatic metabolic activity in patients with hepatic failure.It has been proposed that the drug-metabolizing activity of the liver can be estimated by means of pharmacokinetic analysis after the administration of various probe drugs for CYP isoforms. [8][9][10][11] Matsuo et al. demonstrated that there is a correlation between the CL tot of cyclosporine and the grade severity of liver disease by Child-Pugh classification in patients with hepatitis. 12) However, it is not easy to utilize these approaches to determine the degree of residual hepatic metabolizing ability in patients, as is also the case with creatinine clearance in patients with renal failure.We previously reported that there is a good correlation between mRNA expression and enzyme activity of various CYP isoforms in the livers of rats with acute hepatic failure induced by various doses of CCl 4 . 13) In that study, we also found a good negative correlation between serum aminotransferase activity (AST) and the hepatic activity of each CYP isoform, though the degree of decrease of CL tot varied markedly among CYP isoforms.Here, we present a novel procedure to predict the decrease of CL tot , including that for unknown drugs, based on an increase in serum AST activity in rats with ac...

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Effects of cysteine on the pharmacokinetics of intravenous chlorzoxazone in rats with protein–calorie malnutrition

Cited by 6 publications

References 0 publications

Effects of cysteine on the pharmacokinetics of intravenous chlorzoxazone in rats with protein–calorie malnutrition

Effects of cysteine on the pharmacokinetics of intravenous chlorzoxazone in rats with protein–calorie malnutrition

Effects of cysteine on the pharmacokinetics of itraconazole in rats with protein‐calorie malnutrition

Serum Aminotransferase Activity as a Predictor for Estimation of Total Clearance of Hepatically Metabolized Drugs in Rats with Acute Hepatic Failure

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