Effect of diarrhea on drug disposition

Disease has been shown to alter the disposition parameters of drugs. Few studies have been performed to investigate the effect of diarrhea on the disposition of drugs. Three methods of inducing diarrhea in Long-Evans rats were examined as to their effect on theophylline disposition. Theophylline (10 mg/kg) was administered intravenously through the dorsal vein of the penis under light ether anesthesia and blood samples were collected from the tail tip at appropriate intervals for a total of 12 hours. Theophylline in serum was measured by a high pressure liquid chromatographic method. Disposition parameters of theophylline in control animals were calculated and compared with the values obtained from rats with diarrhea. Rats were fed with a customized lactose diet containing 50[percent] of standard rodent meal and 50[percent] lactose USP. Lactose induced osmotic diarrhea due to the accumulation of undigested lactose in lactase-deficient Long-Evans rats. Statistically significant ( p < 0.05 ) differences were observed in total body clearance of theophylline between treated and control groups. Mean total clearance decreased from 1.46 mL/min/kg body weight in control rats to 1.07 mL/min/kg body weight in diarrheal rats. Volume of distribution decreased from 298 mL/kg body weight in control rats to 270 mL/kg body weight in diarrheal rats. A decrease in the elimination rate constant was also found in the treated animals (0.005192 to 0.004229 min-1). Diarrhea was induced by a single oral dose of 1 mL of castor oil 2 hours before drug administration and by multiple oral doses of 1 mL of castor oil administered 3 hours before, just before and 3 hours after drug dosing. Catharsis was observed 2-3 hours after castor oil dosing and is attributed to the irritant action on the gastrointestinal tract by ricinoleic acid, the fatty acid component of castor oil. No statistically significant differences were observed with single oral dose of castor oil. In the multiple oral doses of castor oil study, decreases were observed in the values for total body clearance of theophylline (2.47 ml/min/kg body weight in controls to 2.29 ml/min/kg body weight in diarrheal rats) and for volume of distribution (from 575 ml/kg body weight to 528.2 ml/kg body weight) and were found to be not statistically significant. Weight loss and per cent loss in weight in individual rats during diarrhea induced by lactose was found to be statistically significant ( p <0.05) when compared to control animals. Mean weight loss was from 13 gm (4.34 per cent) in control rats to 21 gm (7.43 per cent) in diarrheal rats. Similarly statistically significant changes in weight loss and per cent loss in weight were observed with single oral dose of castor oil. The mean weight loss was from 11.5 gm (4.23 per cent) in controls to 15.2 gm (5.63 per cent) in diarrheal rats. Of six rats monitored for the effect of diarrhea induced by multiple oral doses of castor oil, 5 rats had showed consistent decrease in weight loss and increase in per cent loss in weight from controls. The pooled data of the six rats was found to be not statistically significant. Three hundred and thirty micrograms of cholera toxin was administered Intraduodenally under light ether anesthesia. Two hours later, 10 mg/kg dose of theophylline was administered intravenously and blood samples were collected serially over 12 hour period. No diarrheal signs were observed in this study. The effect of cholera toxin on the fluid accumulation in small intestine was studied in rats. Under ethyl carbamate anesthesia the right jugular vein was cannulated and midline Iaprotomy was performed to expose the small intestine. A 20 cm ligated loop of the proximal end of the small intestine was prepared with an indwelling cannula at the proximal end of the loop. Following 10 mg/kg intravenous dose theophylline, 300 pg of cholera toxin or 300p L of saline was injected into the loop and blood samples were collected for a period of 6 hours. At the end of 6 hours, the fluid accumulated in the loops was measured for theophylline concentration. The mean volume of fluid accumulated increased fourteen-fold from 133 pL in controls to 1900 pl in the presence of cholera toxin, the concentration of theophylline in the fluid increased from 3.6 pg/ml to 6.2 pg/ml resulting in twenty four-fold increase in the amount exsorbed into the intestinal lumen from 0.48 pg to 11.8 pg. These investigations have demonstrated the potential for altered disposition parameters of drugs in diarrhea. The findings may be partially due to weight loss and dehydration. In addition, diarrhea may play a role in the exsorption of drugs from the blood into the intestinal lumen and be considered as an important factor in drug disposition and the effect of diarrhea on this process.