Pharmacokinetics of Chlorzoxazone in Rats with Diabetes: Induction of CYP2E1 on 6-Hydroxychlorzoxazone Formation

Baek, Hye W.; Bae, Soo Kyung; Lee, Myung G.; Sohn, Young-Taek

doi:10.1002/jps.20698

Cited by 30 publications

(39 citation statements)

References 26 publications

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“…Similar results for the pharmacokinetics of CZX and OH-CZX and for Cl int per milligram protein have been reported for other rat studies (Baek et al, 2006). Wang et al (2003) also reported that following p.o.…”

Section: Downloaded Fromsupporting

confidence: 75%

“…Liver cirrhosis was also proven, based on histology, as explained under Results. Baek et al (2006) reported that the Cl nr of CZX could represent the metabolic clearance of the drug in rats. Additionally, the Cl nr of CZX listed in Table 3 could represent the hepatic metabolic clearance of CZX.…”

Section: Discussionmentioning

confidence: 99%

“…Kim et al (2005) reported that induction of diabetes mellitus in male Sprague-Dawley rats by treatment with alloxan or streptozotocin (DMIA or DMIS rats, respectively) also increased their protein expression and mRNA level of CYP2E1. Furthermore, Baek et al (2006) reported that the increased protein expression of CYP2E1 caused a significant increase in the formation of OH-CZX in both DMIA and DMIS rats. The association between liver disease and diabetes mellitus is well known (Vidal et al, 1994;Kwon, 2003;Moscatiello et al, 2007).…”

mentioning

confidence: 99%

“…The procedures used were similar to those described by Baek et al (2006). Livers from LC, DM, LCD, and control rats (n ϭ 5, each) were homogenized (Ultra-Turrax T25, Janke and Kunkel; IKA-Labortechnik, Staufeni, Germany) in ice-cold homogenization buffer (0.154 M KCl/50 mM Tris-HCl in 1 mM EDTA, pH 7.4).…”

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confidence: 99%

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Pharmacokinetic Parameters of Chlorzoxazone and Its Main Metabolite, 6-Hydroxychlorzoxazone, after Intravenous and Oral Administration of Chlorzoxazone to Liver Cirrhotic Rats with Diabetes Mellitus

Ahn¹,

Bae²,

Jung³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Protein expression of the hepatic CYP2E1 has been reported to be increased in diabetic rats. This enzyme is the primary metabolizer of chlorzoxazone (CZX) to 6-hydroxychlorzoxazone (OH-CZX). Although patients with liver cirrhosis have a higher prevalence of diabetes mellitus, there have been no reported studies on the protein expression of CYP2E1 in rats induced to have liver cirrhosis and diabetes mellitus by injection of N-dimethylnitrosamine followed by streptozotocin [liver cirrhosis with diabetes mellitus (LCD) rats]. Thus, in the present study, the pharmacokinetics of CZX and OH-CZX were evaluated in LCD rats. Compared with control rats, LCD rats had significantly decreased (by 62%) total liver protein and significantly increased (by 124%) protein expression of CYP2E1, but the intrinsic clearance (Cl int ; formation of OH-CZX per milligram protein) was comparable in both groups of rats. As a result, the relative Cl int was also comparable for the two groups. Thus, OH-CZX formation in LCD and control rats was expected to be similar. As expected, after i.v. (20 mg/kg) and p.o. (50 mg/kg) administration of CZX, the area under the curve (AUC) of OH-CZX was comparable in control and LCD rats (i.v., 571 ؎ 85.8 and 578 ؎ 413 g ⅐ min/ml, respectively; p.o., 1540 ؎ 338 and 2170 ؎ 1070 g ⅐ min/ml, respectively). In LCD rats, the AUC OH-CZX /AUC CZX ratio was similar to the value in control rats after i.v. and p.o. administration. These results indicate that OH-CZX can be used as a chemical probe to assess the activity of CYP2E1 in LCD rats.

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confidence: 75%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Pharmacokinetic Parameters of Chlorzoxazone and Its Main Metabolite, 6-Hydroxychlorzoxazone, after Intravenous and Oral Administration of Chlorzoxazone to Liver Cirrhotic Rats with Diabetes Mellitus

Ahn¹,

Bae²,

Jung³

et al. 2008

Drug Metab Dispos

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“…This was attributed to increased CYP2E1 activity associated with obesity (O'Shea et al, 1994). Animal studies performed using a diabetes mellitus rat model (induced by alloxan or streptozotocin treatment) have reported altered PK of drugs such as acetaminophen, chlorzoxazone, theophylline, clarithromycin, furosemide, and methotrexate (Baek et al, 2006;Kim et al, 2005aKim et al, , 2005bPark et al, 1996Park et al, , 1998Watkins & Sherman, 1992). Although, no changes in PD of atracurium were reported in obese animals compared to lean control (Varin et al, 1990), triazolaminduced sedation in obese humans increased significantly compared to normal weight men (Derry et al, 1995).…”

Section: Pk/pd Studiesmentioning

confidence: 99%

Altered Drug Metabolism and Transport in Pathophysiological Conditions

Gandhi¹,

Ghose²

2012

Topics on Drug Metabolism

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Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine, alone and in combination with diabetes mellitus induced by streptozotocin

Lee

2014

Biopharm & Drug Disp

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Rats with liver cirrhosis induced by N-dimethylnitrosamine (LC) and rats with LC with diabetes mellitus induced by streptozotocin (LCD) have been developed as animal models for human liver cirrhosis and liver cirrhosis with diabetes mellitus, respectively. Changes in the pharmacokinetics of drugs (mainly non-renal clearance, CL NR ) in LC and LCD rats reported in the literature compared with respective control rats were reviewed. This review mainly explains the changes in the CL NR s of drugs (which are mainly metabolized via hepatic microsomal cytochrome P450s, CYPs) in LC and LCD rats, in terms of the changes in in vitro hepatic intrinsic clearance (CL int ; mainly due to the changes in CYPs in the disease state), free (unbound) fraction of a drug in the plasma (f p ) and hepatic blood flow rate (Q H ) depending on the hepatic excretion ratio of the drug. Generally, changes in the CL NR s of drugs in LC and LCD rats could be well explained by the above-mentioned three factors. The mechanism of urinary excretion of drugs (such as glomerular filtration or renal active secretion or reabsorption) in LC and LCD rats is also discussed. The pharmacokinetics of the drugs reported in the LC and LCD rats were scarce in humans. Thus, the present rat data should be extrapolated carefully to humans.

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Pharmacokinetics of Chlorzoxazone in Rats with Diabetes: Induction of CYP2E1 on 6-Hydroxychlorzoxazone Formation

Cited by 30 publications

References 26 publications

Pharmacokinetic Parameters of Chlorzoxazone and Its Main Metabolite, 6-Hydroxychlorzoxazone, after Intravenous and Oral Administration of Chlorzoxazone to Liver Cirrhotic Rats with Diabetes Mellitus

Pharmacokinetic Parameters of Chlorzoxazone and Its Main Metabolite, 6-Hydroxychlorzoxazone, after Intravenous and Oral Administration of Chlorzoxazone to Liver Cirrhotic Rats with Diabetes Mellitus

Altered Drug Metabolism and Transport in Pathophysiological Conditions

Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine, alone and in combination with diabetes mellitus induced by streptozotocin

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