Effects of Acute Renal Failure on the Pharmacokinetics of Chlorzoxazone in Rats

Moon, Young Jin; Lee, Ae Kyung; Chung, Hye Chin; Kim, Eun Jung; Kim, Sohee; Lee, Duk Chul; Lee, Inchul; Kim, Sang Geon; Lee, Myung Gull

doi:10.1124/dmd.31.6.776

Cited by 63 publications

(122 citation statements)

References 37 publications

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“…It has also been reported from our laboratories [115] that CYP2C11 decreased to 80% of the control and CYP3A23 increased by 4 times compared with the control, but the expression of CYP1A2 and CYP2B1/2 was not changed by U-ARF. Therefore, it could be expected that the pharmacokinetics of azosemide could be comparable between the control rats and rats with U-ARF since azosemide was primarily metabolized via CYP1A2 in rats [68].…”

Section: Rats With Diabetes Mellitus Induced By Alloxan (Dmia)supporting

confidence: 70%

Pharmacokinetics and pharmacodynamics of azosemide

Suh¹,

Kim²,

Lee³

2003

Biopharm & Drug Disp

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Azosemide is used in the treatment of oedematous states and hypertension. The exact mechanism of action is not fully understood, but it mainly acts on both the medullary and cortical segments of the thick ascending limb of the loop of Henle. Delayed tolerance was demonstrated in humans by homeostatic mechanisms (principally an increase in aldosterone secretion and perhaps also an increase in the reabsorption of solute in the proximal tubule). After oral administration to healthy humans in the fasting state, the plasma concentration of azosemide reached its peak at 3-4 h with an absorption lag time of approximately 1 h and a terminal half-life of 2-3 h. The estimated extent of absolute oral bioavailability in humans was approximately 20.4%. After oral administration of the same dose of azosemide and furosemide, the diuretic effect was similar between the two drugs, but after intravenous administration, the effect of azosemide was 5.5-8 times greater than that in furosemide. This could be due to the considerable first-pass effect of azosemide. The protein binding to 4% human serum albumin was greater than 95% at azosemide concentrations ranging from 10 to 100 microg/ml using an equilibrium dialysis technique. The poor affinity of human tissues to azosemide was supported by the relatively small value of the apparent post-pseudodistribution volume of distribution (Vdbeta), 0.262 l/kg. Eleven metabolites (including degraded products) of azosemide including M1, glucuronide conjugates of both M1 and azosemide, thiophenemethanol, thiophencarboxylic acid and its glycine conjugate were obtained in rats. Only azosemide and its glucuronide were detected in humans. In humans, total body clearance, renal clearance and terminal half-life of azosemide were 112 ml/min, 41.6 ml/min and 2.03 h, respectively. Azosemide is actively secreted in the renal proximal tubule possibly via nonspecific organic acid secretory pathway in humans. Thus, the amount of azosemide that reaches its site of action could be significantly modified by changes in the capacity of this transport system. This capacity, in turn, could be predictably changed in disease states, resulting in decreased delivery of the diuretic to the transport site, as well as in the presence of other organic acids such as nonsteroidal anti-inflammatory drugs which could compete for active transport of azosemide. The urinary excretion rate of azosemide could be correlated well to its diuretic effects since the receptors are located in the loop of Henle. The diuretic effects of azosemide were dependent on the rate and composition of fluid replacement in rabbits; therefore, this factor should be considered in the evaluation of bioequivalence assessment.

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Section: Rats With Diabetes Mellitus Induced By Alloxan (Dmia)supporting

confidence: 70%

Pharmacokinetics and pharmacodynamics of azosemide

Suh¹,

Kim²,

Lee³

2003

Biopharm & Drug Disp

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“…The total injection volume was 2 ml/kg. Approximately 0.22 ml aliquot of blood sample was collected via the carotid artery at 0 (to serve as a control), 1 (at the end of the infusion), 3,7,15,30,40,50, 60, 70 and 80 min after intravenous administration of omeprazole. Approximately 0.25 ml aliquot of the heparinized 0.9% NaCl-injectable solution (20 units/ml) was used to flush the cannula after each blood sampling to prevent blood clotting.…”

Section: Intravenous Studymentioning

confidence: 99%

Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous omeprazole in rats

Lee

Shin

Bae

et al. 2006

Biopharm & Drug Disp

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A series of experiments using various inducers and inhibitors of the hepatic microsomal cytochrome P450 (CYP) isozymes were conducted to find CYP isozymes responsible for the metabolism of omeprazole in male Sprague-Dawley rats. Omeprazole, 20 mg/kg, was administered intravenously. In rats pretreated with SKF 525-A (a nonspecific CYP isozyme inhibitor in rats), the time-averaged nonrenal clearance (Cl(nr)) was significantly slower (77.1% decrease) than that in untreated rats. This indicated that omeprazole is metabolized via CYP isozymes in rats. Hence, rats were pretreated with various enzyme inducers and inhibitors. In rats pretreated with 3-methylcholanthrene and dexamethasone (main inducers of CYP1A1/2 and 3A1/2 in rats, respectively), the Cl(nr) values were significantly faster (43.8% and 26.3% increase, respectively). In rats pretreated with troleandomycin and quinine (main inhibitors of CYP3A1/2 and 2D1 in rats, respectively), the Cl(nr) values were significantly slower (20.9% and 12.9% decrease, respectively). However, the Cl(nr) values were not significantly different in rats pretreated with orphenadrine, isoniazid and sulfaphenazole (main inducers of CYP2B1/2 and 2E1, and a main inhibitor of 2C11, respectively, in rats) compared with those of respective control rats. The above data suggested that omeprazole could be mainly metabolized via CYP1A1/2, 3A1/2 and 2D1 in male rats.

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“…Formation of OH-CZX from CZX is primarily catalyzed by the hepatic microsomal cytochrome P450 (P450) enzyme 2E1 in humans (Conney and Burns, 1960) and rats (Rockich and Blouin, 1999;Moon et al, 2003). OH-CZX formation has been used as a chemical probe to assess the activity of CYP2E1 in vitro and in vivo because of its good correlation with CYP2E1 activity in humans (Peter et al, 1990) and rats (Rockich and Blouin, 1999).…”

mentioning

confidence: 99%

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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Effects of Acute Renal Failure on the Pharmacokinetics of Chlorzoxazone in Rats

Cited by 63 publications

References 37 publications

Pharmacokinetics and pharmacodynamics of azosemide

Pharmacokinetics and pharmacodynamics of azosemide

Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous omeprazole in rats

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

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