Pharmacology zyxwvutsrqpo & Toxicology zyxwvutsrqpo 1990, 66, 361-366. zyxwvutsr The zyxwv Effects of Age and Dietary Protein Restriction on the Pharmacokinetics of Theophylline in the Rat zy Donald Jug* and Maulik Nanavaty Department of Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, U.S.A. (Received July 10, 1989; Accepted November 27, 1989) Absrrucr: The influence of dietary protein levels on theophylline kinetics was examined in male Fischer 344 virgin rats of 2, 14 and 20 months of age fed for four weeks on a 23% (control) or zyxwvu 5% (low) protein diet ad libitum. Protein deficiency led to a significant decrease in body weight gain for the 2 month old rats (10.9% versus 26.5%). In addition, decreases in total body weight of 7.5% and 15.3% were seen for the 14 and 20 month old rats, respectively, on a low protein diet. Total proteins and albumin levels in plasma were not significantly affected by age or dietary protein levels. After intravenous administration of 10 mg/kg aminophylline, the average mean residence time (MRT) was significantly longer in 20 month old rats as compared to the younger rats, while 14 month old rats had a greater elimination rate constant than the 2 and 20 month old rats. There were significant reductions in the mean steady-state apparent volume of distribution (Vss) in the 2 and 14 month old rats on a low protein diet of 31% and 18%, respectively, while there was no difference between the diets in 20 month old rats. In addition, the Vss decreased from 0.71 L/kg to 0.57 L/kg in the 2 and 20 month old rats, respectively, on a normal protein diet. Dietary protein deficiency led to a significant reduction of total body clearance from approximately 73 to 45 ml/hr/kg in the 2 and 14 month old rats. Interestingly, although there appeared to be a diet-related impairment of theophylline metabolism in the younger rats, theophylline clearance was approximately 45 ml/hr/kg in the 20 month old rats, irrespective of dietary protein level. In recent years, there has been growing interest in the effects of advanced age on drug disposition in man (Triggs & Nation 1975; Crooks er af. 1976; Richey & Bender 1976). It is generally accepted that the increased sensitivity to drugs in old age is a result of age-related changes in pharmacody- namics and/or pharmacokinetics. Numerous investigators have shown that age-related differences in drug disposition may be the result of progressive physiological alterations as well as functional changes in drug distribution, metabolism, excretion and blood flow. Nutritional influences on drug action is only just begin- ning to be investigated. Drug-nutrient interactions have been increasingly important for the majority of the popula- tion in the world because of malnutrition, specifically, prote- in-calorie malnutrition (PCM). While PCM is a major health problem in Third World countries, it occurs to some extent even in industrialized nations. In the United States, PCM may be present in up to 50% of hospitalized medical patients (Bistrian er af. 1974 & 1976; Willard et zyxwvuts al. 1980). Recent in vitro and in vivo studies have shown that dietary factors and nutritional status considerably influence the absorption, plasma protein binding, distribution, biotrans- formation and excretion of drugs (Campbell & Hayes 1976; Dickerson et al. 1976; Krishnaswamy 1978). Although PCM is most prevalent in young children, it can develop at any age whenever there is prolonged consumption of a diet high in carbohydrate and low in protein. The elderly are particularly at risk for malnutrition. Elderly (individuals * Present address: Syntex Research, 3401 Hillview Avenue, A3- 165, Palo Alto, CA 94304, U S A . over 65 years of age) may have poor food habits and con- sume diets nutritionally inadequate with respect to vitamins, minerals and proteins. The present investigation was undertaken to determine the effect of aging and dietary protein levels on hepatic oxidative metabolism in an animal model of marasmic kwashiorkor, namely, the rat (Kirsch et al. 1968). The distri- bution and elimination of theophylline, a model drug for the study of phase I hepatic oxidative drug metabolism, in rats at three different ages was used to elucidate factors affecting age and diet-related pharmacokinetics of theophyl- line. Materials and Methods Male Fischer 344 virgin rats of 2, 14 and 20 months of age at the beginning of the study were obtained from NIH-NIA aging colonies maintained by Harlan Sprague Dawley, Inc., Indianapolis, IN, U.S.A. The animals were randomly allocated to one of two diets containing either 23% (control) or 5% (low) protein for four weeks as previously described (Jung 1985a & b; Jung et al. 1985; Jung & Shah 1986). Diets were isocaloric and purchased in pellet form from Teklad (Madison, WI, U.S.A.). All rats were allowed food and water ad libitum. Food intake and body weights were recorded at least once a week. At the end of four weeks, the right jugular vein was catheterized with silastic tubing under light ether anaesthesia. All animals were housed individually in plastic metabolism cages and allowed to recover overnight. Aminophylline (Invenex, Ohio Falls, OH, U.S.A.), 10 mg/kg) in normal saline was administered by intra- venous injection over 30 sec. into the jugular vein. Blood (0.1 ml) was collected via the jugular vein cannula at 0, 5, 15, 30 min. and at I, 1.5,2, 3,4, 5, 6, 8, 12, 16 and 24 hr following drug administra-