Effects of water deprivation for 72 hours on the pharmacokinetics of a new carbapenem, DA-1131, in rats

Abstract

Hormonal, physiological, and biochemical changes occurring in dehydrated patients could alter the pharmacokinetics of the drugs; therefore, the pharmacokinetics of DA-1131, a new carbapenem antibiotic, were investigated after 1-min intravenous administration of the drug at 50 mg/kg to control and 72-hr water-deprived rats. The impaired kidney and liver functions were observed in water-deprived rats on the basis of tissue microscopic examination. After intravenous infusion of the drug to water-deprived rats, the plasma concentrations of DA-1131 were higher and this resulted in a significantly greater total area under the plasma concentration-time curve from time zero to time infinity than those in control rats (4520 versus 3760 μg min/ml). This could be due to significantly slower total body clearance (CL) of DA-1131 in water-deprived rats (9.81 versus 14.1 ml/min/kg). The significantly slower CL of DA-1131 in water-deprived rats was due to significant decrease in both renal clearance (2.87 versus 5.13 ml/min/kg because of a significant decrease in 8-hr urinary excretion of unchanged DA-1131 [28.4 versus 39.9% of the intravenous dose] due to impaired kidney function) and nonrenal clearance (6.82 versus 8.66 ml/min/kg because of a significant decrease in the metabolism of DA-1131 in the kidney, as proved by the significant decrease in total renal DHP-I enzyme activity [1900 versus 2130 mU/each kidney]) in water-deprived rats. Water-deprivation did not alter the affinity of rat tissues to DA-1131.