Influence of Short-Term Water Deprivation on Kinetics of Trimethadione and Its Metabolite in Rats

The following results were obtained recently from our laboratories; in rats with 72-h water deprivation (rats with dehydration), the hepatic cytochrome P450 2E1 (CYP2E1) was three-fold induced with an increase in the mRNA. Rehydration of 48-h water-deprived rats for the next 24 h with free access of food (rats with rehydration) restored CYP2E1 level to that of control. However, rehydration of 48-h water-deprived rats for the next 24 h with limited food supply (20% of control) failed to restore the CYP2E1 level to that of control. Hence, the CYP2E1 changes in rats with dehydration and rehydration resulted from differences in food intakes but not from dehydration or rehydration per'se. Chlorzoxazone (CZX) is metabolized to 6-hydroxychlorzoxazone (OH-CZX) mainly by CYP2E1 in rats. Therefore, the pharmacokinetics of CZX and OH-CZX were compared after intravenous administration of CZX, 25 mg/kg, to control rats and rats with dehydration and rehydration with free access of food. In rats with dehydration, the amount of 24-h urinary excretion of free OH-CZX plus its glucuronide conjugates (Ae (OH-CZX, 0-24 h,) expressed in terms of intravenous dose of CZX) was significantly greater (45.6 compared with 35.6%) and area under the plasma concentration-time curve from time zero to time infinity (AUC) of CZX was significantly smaller (2190 compared with 3200 micro g min/ml) than those in control rats. The above data indicated that the formation of OH-CZX increased significantly in rats with dehydration due to 3-fold induction of CYP2E1. In rats with rehydration with free access of food, the Ae (OH-CZX, 0-24 h) (39.0 compared with 35.6%) and AUC of CZX (2870 compared with 3200 micro g min/ml) were restored (comparable) to control levels since the expression of CYP2E1 in rats with dehydration returned to control level by rehydration. The above data indicate that CZX could be used as a chemical probe to assess the activity of CYP2E1 in rats with dehydration and rehydration.

Section: Discussionsupporting

confidence: 55%

Pharmacokinetics of intravenous chlorzoxazone in rats with dehydration and rehydration: effects of food intakes

Kim

et al. 2003

“…Similar results were also obtained from other rat studies [7]. Food intake also decreased significantly in the rat model of dehydration (Tables 1, 3 and 4) and similar results were also reported from other rat studies [6,7,10,11,23,24]. The smaller body weight gain in the rat model of dehydration could be due to the lower food intake to prevent elevations in the extracellular fluid osmolarity and sodium concentration [6] in addition to water deprivation.…”

Section: Discussionsupporting

confidence: 88%

Effects of water deprivation on the pharmacokinetics of metformin in rats

Choi

Lee

2007

It was reported that metformin was mainly metabolized via hepatic CYP2C11, 2D1 and 3A1/2 in rats, and in a rat model of dehydration, the expressions of hepatic CYP2C11 and 3A1/2 were not changed. Hence, it could be expected that the Cl(nr) of metformin is comparable between two groups of rats if the contribution of CYP2D1 in the rat model of dehydration is not considerable. It was also reported that the timed-interval renal clearance of metformin was dependent on the urine flow rate in rats. In the rat model of dehydration, the 24 h urine output was significantly smaller than in the controls. Hence, the urinary excretion of metformin was expected to be smaller than the controls. The above expectations were proven as follows. After intravenous administration of metformin (100 mg/kg) to the rat model of dehydration, the Cl(nr) were comparable between the two groups of rats. After both intravenous and oral administration of metformin (both 100 mg/kg) to the rat model of dehydration, the 24 h urinary excretion of the drug was significantly smaller than in the controls. After oral administration of metformin to the rat model of dehydration, the AUC was significantly greater (99.2% increase) than the controls.

“…Food intake also decreased significantly in rat model of dehydration (56.0% and 43.5% decrease for intravenous and oral administration, respectively) ( Table 2). Similar results have also been reported from other rat studies [5,9,24,25]. Hence, the decrease in body weight gain could be due to less food intake to prevent elevations in extracellular fluid osmolarity and sodium concentration [5] in addition to water deprivation in rat model of dehydration.…”

Section: Discussionsupporting

confidence: 86%

Effects of water deprivation on the pharmacokinetics of theophylline and one of its metabolites, 1,3‐dimethyluric acid, after intravenous and oral administration of aminophylline to rats

Choi

Kang

Chung

et al. 2007

It has been reported that the expressions of hepatic microsomal cytochrome P450 (CYP) 1A1/2, 2B1/2 and 3A1/2 were not changed in rats with water deprivation for 72 h (rat model of dehydration) compared with the controls. It has been also reported that 1,3-dimethyluric acid (1,3-DMU) was formed from theophylline via CYP1A1/2 in rats. Hence, it could be expected that the formation of 1,3-DMU could be comparable between the two groups of rats. As expected, after both intravenous and oral administration of theophylline at a dose of 5 mg/kg to the rat model of dehydration, the AUC of 1,3-DMU was comparable to the controls. After both intravenous and oral administration of theophylline to the rat model of dehydration, the Cl(r) of both theophylline and 1,3-DMU was significantly slower than the controls. This could be due to significantly smaller urinary excretions of both theophylline and 1,3-DMU since the AUC of both theophylline and 1,3-DMU were comparable between the two groups of rats. The smaller urinary excretion of both theophylline and 1,3-DMU could be due to urine flow rate-dependent timed-interval renal clearance of both theophylline and 1,3-DMU in rats.