Diet and Cimetidine Induce Comparable Changes in Theophylline Metabolism in Normal Subjects K.E. ANDERSON, R.B. MCCLEERY, E.S. VESELL, F.F. VICKERS, A. KAPPAS Hepatology 13:941–946, 1991

Abstract

This study examines the effects of diet and cimetidine on theophylline metabolism in 12 men. Subjects, all nonsmokers within 15% of their ideal body weight, were 23 to 26 years of age and had no unusual dietary habits. Energy needs were calculated using the Harris‐Benedict equation. Subjects were placed either on a high‐protein, low‐carbohydrate diet (44% of total calories as protein, 35% as carbohydrate, and 21% as fat) or a low‐protein, high‐carbohydrate diet (10% of total calories as protein, 70% as carbohydrate, and 20% as fat) for 15 days on each diet. The order of the dietary periods was reversed in one half of the subjects, and there was a 24‐day washout period between the two dietary periods. Cimetidine (800 mg/d at bedtime) was administered on days 10 to 15 of each dietary period. Aminophylline (3 mg of theophylline base/kg body weight) was administered intravenously as a bolus over 20 to 30 minutes on days 8 and 15 of each dietary period. Blood was withdrawn before and at 1, 2, 4, 6, 8, 12, and 24 hours after the end of the infusion for determination of theophylline plasma levels by high‐pressure liquid chromatography. Theophylline metabolism was studied under four experimental conditions in all 12 subjects. Thus, the effect of: (1) diet change (changing from a high‐progein to a high‐carbohydrate diet), (2) diet change during concurrent cimetidine administration, (3) cimetidine during a high‐protein diet, and (4) the combination of cimetidine and the opposite change in diet (from high carbohydrate to high protein) were examined.Diet change (high protein to high carbohydrate) reduced mean theophylline clearance by 30 ± 10% (p < 0.012). Diet change (high protein to high carbohydrate) during concurrent cimetidine administration, resulted in 23 ± 9% reduction in theophylline clearance (p < 0.016). During a high‐protein diet, cimetidine decreased mean theophylline clearance by 37 ± 5% (p < 0.0009). During a high‐carbohydrate diet, cimetidine decreased theophylline clearance by 30 ± 5% (p < 0.0014). Depending on the direction of change in the protein/carbohydrate ratio, the effects of diet and cimetidine were either additive (theophylline clearance was slower during a high‐carbohydrate diet and cimetidine administration) or counteractive (an increase in the protein/carbohydrate ratio partially counteracts the inhibitory effect of cimetidine).The authors conclude that diet and drugs can have similar effects on hepatic drug metabolism rates in humans. Therefore, during treatment with a drug having a narrow therapeutic index, it would be important to consider not only potential drug‐drug interactions but also drug‐diet interactions. Such interactions could result in either subtherapeutic or excessive drug levels.