Absorption and disposition kinetics of chlorothiazide in protein-calorie malnutrition

The influence of dietary protein deficiency on the absorption and disposition kinetics of chlorothiazide was investigated in male Sprague-Dawley rats fed for 4 weeks on a 23 per cent (control) or a 5 per cent (low) protein diet ad libitum. Chlorothiazide in plasma and urine was determined by a sensitive and specific HPLC assay. Following an intravenous dose of 10 mg kg-1 chlorothiazide, there was a significant decrease in the total plasma clearance (Cl) per kg of body weight from 1.80 +/- 0.15 to 1.29 +/- 0.15 l h-1 kg-1 and apparent steady-state volume of distribution from 0.65 +/- 0.13 to 0.38 +/- 0.07 l kg-1 in the protein-deficient rats. However, no significant difference was found in the two groups of animals with respect to mean residence time (MRT) and free fraction of drug in plasma. The mean harmonic half-life was increased from 72 to 91 min in the protein-deficient rats. The urinary recovery of unchanged chlorothiazide in 48 h was essentially complete in both groups of animals. The absorption of chlorothiazide, as assessed by the mean urinary recovery of unchanged drug after oral administration, was 66 per cent and 68 per cent in normal and protein-deficient rats, respectively.