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Obesity and fasting—effects on drug metabolism and drug action in man
Author(s) -
Reidenberg Marcus M.
Publication year - 1977
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt1977225part2729
Subject(s) - tolbutamide , volume of distribution , endocrinology , medicine , pharmacokinetics , chemistry , diabetes mellitus
Drug metabolism and distribution were studied in severely obese subjects who underwent a 2‐wk fast as part of a weight reduction program. Drug studies were done before fasting and repeated during the fast after ketoacidosis had developed and weight loss had occurred. The half‐life values of 5 drugs—antipyrine and tolbutamide metabolized by the microsomal oxidation pathway, sulfisoxazole and isoniazid by acetylation, and procaine by the pseudocholinesterase hydrolysis pathway—were found to be normal in the obese but otherwise healthy subjects when allowance was made for the body weight. The dose‐response curve, as demonstrated by the effect of atropine, 0.24 mg every 4 min given intravenously, on the heart rate was the same in obese as in normal weight subjects when the dose was calculated on a weight basis. The apparent volumes of distribution of antipyrine and tolbutamide and the metabolic clearance rates were normal, again if corrected for body size. In some patients (those with edema) a discontinuity was noted in the plasma elimination curve of tolbutamide, apparently because of a decrease in the volume of distribution of this protein‐bound drug when the subjects changed from the recumbent to the sitting position. The same effect had been reported by others with protein‐bound sulfonamides and benzylpenicillin during change from the recumbent to the upright posture, an effect to be considered in interpreting pharmacokinetic data. Fasting for 7 to 10 days decreased the volume of distribution in proportion to the loss of weight and body water. The excretion rate of sulfisoxazole was decreased by fasting, one reason being that fasting caused a decrease in urine flow rate and a fall in pH, both favoring nonionic diffusion of the drug from the renal tubule back to the blood. Regardless of the different transformation pathways, the rate of metabolism of the drugs studied remained unchanged by fasting. This observation is in sharp contrast to changes seen in laboratory animals, varying with the species, sex, and drug substrate used among other factors. Extrapolations of data from species to species concerning the effects of fasting on drug metabolism may, therefore, lead to erroneous conclusions.