Effects of water deprivation for 72 hours on the pharmacokinetics of DA-7867, a new oxazolidinone, in rats

Abstract

The pharmacokinetic parameters of DA-7867 were compared after intravenous and oral administration at a dose of 10 mg/kg in control rats and in rats with water deprivation for 72 h (rat model of dehydration). After intravenous administration in the rat model of dehydration, the Cl(nr) (0.654 versus 0.992 ml/min/kg) and Cl(r) (0.0273 versus 0.0784 ml/min/kg) values were significantly slower than in the controls. The slower Cl(nr) could be due mainly to a significantly smaller total amount of unchanged DA-7867 recovered from the gastrointestinal tract at 24 h (GI(24 h): 5.16% versus 9.21% of intravenous dose) due to impaired liver function in the rat model of dehydration. The slower Cl(r) could be due mainly to a significantly smaller 24 h urinary excretion of unchanged drug (Ae(0-24 h): 4.41% versus 7.75% of intravenous dose) due to urine flow rate-dependent Cl(r) of DA-7867 in the rat model of dehydration. Hence, the Cl was significantly slower in the rat model of dehydration (0.677 versus 1.07 ml/min/kg). After intravenous administration in the rat model of dehydration, the V(ss) of DA-7867 was significantly smaller than in the controls (396 versus 506 ml/kg) due mainly to significantly smaller free (unbound to plasma proteins) fractions of DA-7867 in plasma (6.90% versus 29.2%) in the rat model of dehydration. After oral administration in the rat model of dehydration, the AUC was significantly greater than that in controls (10800 versus 7060 microg min/ml) due mainly to a significantly smaller Ae(0-24 h) than in controls (3.50% and 6.17% of oral dose).

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

“…Induction of dehydration was evident based on the significantly smaller 24 h urine output (88.0% and 94.4% decrease for intravenous and oral administration, respectively) and significant decrease in body weight gain (from 257 to 253 g versus from 255 to 281 g and from 301 to 279 g versus from 293 to 313 g for intravenous and oral administration, respectively) in the rat model of dehydration (Table 2). Similar results have also been reported from other rat studies [9]. Food intake also decreased significantly in rat model of dehydration (56.0% and 43.5% decrease for intravenous and oral administration, respectively) ( Table 2).…”

“…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.…”

“…Urine flow rate-dependent timedinterval renal clearance of theophylline has also been obtained from humans [6,7,22]. The 24 h urine output was significantly smaller in the rat model of dehydration than in the controls in the present (Table 2) and other rat [5,9] studies. Kidney function was reported to be impaired in the rat model of dehydration [30,31].…”

“…Therefore, it could be expected that the time-averaged renal clearance (Cl r ) of theophylline could be slower in the rat model of dehydration. Although pharmacokinetic changes of drugs in the rat model of dehydration have been reported [9], studies on theophylline with respect to CYP isozyme changes in rat model of dehydration [5] do not seem to have been reported. Moreover, it has been reported that hypoxia, dehydration, acidosis and hypokalemia render the severe asthmatic patient vulnerable to cardiac dysrhythmia and cardiorespiratory arrest [10].…”

“…It has been reported that the timedinterval renal clearance of theophylline was dependent on urine flow rate in children with asthma [6] and healthy adults [7] and of 1,3-DMU in pediatric patients [8]. Urine output was significantly smaller in the rat model of dehydration [4,5,9]. Therefore, it could be expected that the time-averaged renal clearance (Cl r ) of theophylline could be slower in the rat model of dehydration.…”