Summary
The genetically obese Zucker rat was used as a model of obesity and compared to its lean littennate to assess and quantify obesity-altered changes in the in vivo disposition of six sulfonamides. Body composition determination indicated that the obese rats-were twice the weight of lean rats and a distinct trend towards an increase in fat free mass and total body water was observed. The sulfonamide blood concentration was measured by colorimetry after a 7 mg/kg intravenous dose. All sulfonamides exhibited a biexponential decline of blood concentration with time. The volume of distribution and clearance of sulfanilamide in lean and obese rats were similar resulting in similar elimination half-lives. A decrease in clearance coupled with a trend towards an increase in volume of distribution prolonged the elimination half-life of sulfadiazine in obese rats. For sulfapyridine, sulfamerazine, sulfisomidine and sulfisoxazole, increases in the volumes of distribution and clearances resulted in similar elimination half-lives in lean and obese rats. The free fractions of the sulfonamides were significantly increased in the serum of obese rats, the influence of which on the volume of distribution and clearance is discussed.
Similar content being viewed by others
References
Merritt R.J. (1982): Obesity. Curr. Probl, Pediatr., 12, 1–58.
Bray G.A. (1979): Obesity. Disease-a-Month, 26, 7–83.
Gundersen K., Shen G. (1966): Total body water in obesity. Am. J. Clin. Nutr., 19, 77–83.
Pierson R.N., Jr., Wang J., Yang M.U., Hashim S.A., van Itallie T.B. (1976): The assessment of human body composition during weight reduction: Evaluation of a new model for clinical studies. J. Nutr., 106, 1694–1701.
Womersley J., Dumin J., Boddy K., Mahaffy M. (1976): Influence of muscular development, obesity and age on the fat free mass of adults. J. Appl. Physiol. 41, 273–279.
Riegelman S., Loa J.C.K., Rowland M. (1968): Shortcomings in pharmacokinetic analysis by conceiving the body to exhibit properties of a single compartment. J. Phann. Sci., 57, 117–123.
Alexander J.K., Dennis E.W., Smith W.G., Ahmad K.H., Duncan C., Austin R.C. (1962–63): Blood volume, cardiac output and distribution of systemic blood flow in extreme obesity. Cardiovasc. Res. Cent Bull., 2, 39°644.
Benedek I.H., Fiske W.D., Ill, Griffen W.O., Jr., Blouin R.A., McNamara P.J. (1983): Serum protein binding of drugs in obesity. Presented at the l30th Annual Meeting of the American Pharmaceutical Association, New Orleans, Louisiana, April 9–14.
Adler M., Schaffner F. (1979): Fatty liver hepatitis and cirrhosis on obese patients. Am. J. Med., 67, 811–816.
Litterst C.L. (1980): In vitro hepatic drug metabolism and microsomal enzyme induction in genetically obese rats. Biochem. Pharmacol., 29, 289–296.
Berstein R.A., Werner L.H., Rimm A.A. (1973): Relationship of gallbladder disease t parity, obesity and age. Health Serv. Rept., 88, 925–936.
Gordon T., Castelli W.P., Hjortland M.C., Kannel W.B., Dawber T.R. (1977): Diabetes, blood lipids and the role of obesity in coronary heart disease risk for women. The Framingham Study, Am. Intern. Med., 87, 393–397.
Pettersen P. (1977): Fatty liver in patients with moderate liver complications, alcohol consumption, diabetes mellitus and overweight. Scand. J. Gastroenterol., 12, 781–784.
Bierman E.L., Bagdade J.D., Porte D., Jr, (1968): Obesity and diabetes: The odd couple. Am. J. Clin. Nutr., 21, 1434–1437.
Wright R.A., Krinsky S., Fleeman C., Trujillo J., Teague E. (1983): Gastric emptying and obesity. Gastroenterology, 84, 747–751.
Horowitz M., Collins P.J., Harding P.E., Sherman D.J.C. (1983): Abnormalities of gastric emptying in the obese patient. Int. J. Obesity, 7, 415–421.
Stokholm K.H., Brochner-Mortensen J., Hoilund-Carlsen P.F. (1980): Increased glomerular filtration rate and adrenocortical function in obese women. Int. J. Obesity, 4, 57–63.
Hunt J.N., Cash R., Newland P. (1975): Energy density of food, gastric emptying and obesity. Lancet, 2, 905–906.
Abernethy D.R., Greenblatt D.J. (1982): Pharmacokinetics of drugs in obesity. Clin. Phannacokinet., 7, 108–124.
Shum L., Jusko W.J. (1984): Theophylline disposition in obese rats. J. Phannacol. Exp. Ther., 228, 380–386.
Rowse K.L., Kostenbauder H.B., McNamara P.J., Blouin R.A. (1983): Pharmacokinetics of phenobarbital in obese Zucker, lean Zucker and Sprague-Dawley rats. Presented at the Both Annual Meeting of the American Pharmaceutical Association, New Orleans, Louisiana, April 9–14.
Zucker L.M., Zucker T.F. (1961): Fatty, a new mutation in the rat. J. Hered., 52, 275–278.
Bray G.A., York D.A. (1977): Genetically transmitted obesity in rodents. Physiol. Rev., 51, 599–646.
Bray G.A., (1977): The ZUcker-fatty rat: a review. Fed. Proc., 36, 148–153.
Kodama A.M. (1971): In vivo and in vitro detertninations of body fat and body water in the hamster. J. Appl. Physiol., 31, 218–222.
Kaul S., Ritschel W.A. (1987): Free fatty acids and the binding of sulfonamides in the serum of genetically obese Zucker rat Methods Find. Exp. Clin. Pharmacol. 9, 317–320.
Bratton A.C., Marshall E.K., Jr. (1939): A new coupling component for sulfanilamide determination. J. Biol. Chem., 128, 537–550.
Rothwell N.J., Stock M.J. (1979): In vivo determination of body composition by tritium dilution in the rat. Br. J. Nutr., 41, 625–628.
Light A.E., Smith P.K., Smith A.H., Anderson W.E. (1934): Inorganic salts in nutrition. XI. Changes in composition of the whole animal induced by a diet poor in salts. J. Biol. Chem., 107, 689–695.
Ashworth U.S., Cowgill G.R. (1938): Body composition as a factor governing the basal heat production and the endogenous nitrogen excretion. J. Nutr., 15, 73–81.
Widdowson E.M., Dickerson J.W.T. (1968): Chemical composition of the body, In: Comar C.L., Bonner F. eds. Mineral Metabolism, Vol. 2, Part A. New York: Academic Press, pp. 1–247.
Tisavipat A., Vibulsreth S., Sheng H-P., Huggins R.A. (1974): Total body water measured by desiccation and by tritiated water in adult rats. J. Appl. Physiol., 37, 699–701.
Metzler C.M., Elfring G.L., McEwen A.J. (1974): A package of computer programs for phannacokinetic modeling. Biometrics, 30, 562–563.
Wagner J.G. (1976): Linear pharmacokinetic equations allowing direct calculation of many needed pharmacokinetic parameters from the coefficients and exponents of polyexponential equations which have been fitted to the data. J. Pharmacokinet Biopharm., 4, 443–467.
SAS Package (1982): Statistical Analysis System Institute, Inc., Cary, North Carolina.
Foy I.M., Schneiden H. (1960): Estimation of total body water (virtual tritium space) in the rat, cat, rabbit, guinea pig and man, and of the biological half-life of tritium in man. J. Physiol., 154, 169–176.
Raison J., Achimastos A., Bouthier J., London G., Safar M. (1983): Intravascular volume, extracellular fluid volume and total body water and non-obese hypertensive patients. Am. J. Cardiol., 51, 165–170.
Mendex J., Kollias J. (1977): Diet and starvation on the composition and calculated density offat-free body mass. J. Appl. Physiol. 42, 731–734.
Fidenza F., Keys A., Anderson J.T. (1953):; Density of body fat in man and other animals. J. Appl. Physiol., 6, 252–256.
Spector W.S. (1956): Handbook of Biological Data, Philadelphia: Saunders, p. 340.
Yacobi A., Levy G. (1979): Effect of serumprotein binding on sulfisoxazole distribution, metabolism and excretion in rats. J. Pharm. Sci., 68, 742–746.
Marshall E.K., Jr. (1948): Distribution of 3,4- dimethyl-5-sulfanilarnidoisoxazole in the body. Proc. Soc. Exp. BioI. Med., 68, 472–473.
Kaplan S.A., Weinfeld R.E., Abruzzo C.W., Lewis M. (1972): Pharmacokinetic profile of sulfisoxazole following intravenous, intramuscular and oral administration to man. J. Pharm. Sci., 61, 773–778.
Gibaldi M., Koup J.R. (1981): Pharmacokinetic conceptsdrug binding, apparent volume of distribution and clearance. Bur. J. Clin. Pharmacol., 20, 299–305.
Branch R.A., Jones J., Read A.E. (1976): A study offactors influencing drug disposition in chronic liver disease, using the model drug (+)-propranolol. Br. J. Clin. Pharmacol., 3, 243–249.
MacNamara P.J., Gibaldi M., Stoeckel K. (1983): Fraction unbound in interstitial fluid. J. Pharm. Sci., 72, 834–836.
Thompson G.A. (1983):Influence of Cimeudine on Bupivacaine Disposition, Ph.D. Dissertation, University of Cincinnati, Cincinnati, Ohio.
Abernethy D.R., Greenblatt D.J., Divoll M., Harmatz J.S., Shader R.I. (1981): Alterations in drug distribution and clearance due to obesity. J. Pharmacol. Exp. Ther., 217, 681–685.
Abernethy, D.R., Greenblatt D.J., Divoll M., Shader R.I. (1982): Prolongation of half-life due to obesity: Studies of desmethyldiazepam (chlorazepate). J. Pharm. Sci., 71, 942–944.
Abernethy D.R., Greenblatt D.J., Divoll M., Shader R.I. (1983): Prolonged accumulation of diazepam in obesity. J. Clin. Pharmacol., 23, 369–376.
Garrett E.R., Silverkrup R.S., Eberst K., Yost R.L., O’Leary J.P. (1981): Surgically affected sulfisoxazole pharmacokinetics in morbidly obese. Biopharm. Drug Dispos., 2, 329–365.
Altman P.L., Dittner D.S. (1974): Biology Data Handbook, 2nd Edn, Vol. III, Federation of American Societies for Experimental Biology, Bethesda, Maryland, p. 1702.
Rowland M., Tozer T.N. (1980): Clinical Pharmacokinetics: Concepts and Applications, Philadelphia: Lea & Febiger, pp. 48–76.
Wilkinson G.R., Shand D.G. (1975): A physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther., 18, 377–390.
Gugler R., Shoeman D.W., Huffman D.H. Cohlinia J.B., Azarnoff D.L. (1975): Pharmacokinetics of drugs in patients with nephrotic syndrome. J. Clin. Invest., 55, 1182–1186.
Levy G., Yacobi A. (1974): Effect of plasma protein binding on elimination of warfarin. J. Pharm. Sci., 63, 805–806.
Trenk D., Jähnchen E. (1980): Effect of serum protein binding on pharmacokinetics and anticoagulant activity of phenprocoumon in rats. J. Pharmacokinet. Biopharm., 8, 177–191.
Schary W.L., Rowland M. (1983): Protein binding and hepatic clearance: Studies with tolbutamide, a drug of low intrinsic clearance, in isolated perfused rat liver preparation. J. Pharmacokinet. Biopharm., 11, 225–243.
Rowland M., Leitch D.S., Fleming G., Smith B. (1983): Protein binding and hepatic extraction of diazepam across the rat liver. J. Pharm. Pharmacol., 35, 383–384.
Zucker T.F., Zucker L.M. (1962): Hereditary obesity in the rat associated with high serum fat and cholesterol. Proc. Soc. Exp. BioI. Med., 110, 165–171.
Windholz M. (Ed.) (1983): The Merck Index, Merck & Co., Rahway, New Jersey, pp. 8774–8835.
Scudi J.V., Jelinek V.C. (1944): A distribution method for the differentiation of urinary excretion products of the sulfonamide drugs and the role of these products in urolithiasis. J. Pharmacol. Exp. Ther., 81, 218–223.
Anton A.H., Boyle J.J. (1964): Alteration of the acetylation of sulfonarnides by protein binding, sulfmpyrazone and suramin. Can. J. Physiol. Pharmacol., 42, 809–817.
Heel R.C., Avery G.S. (1980) In: Avery G.S., ed. Drug Treatment. New York: Adis Press, pp. 1121–1224.
Leo A., Hansch C., Elkins D. (1971): Partition coefficients and their uses. Chem. Rev., 71, 525–616.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kaul, S., Ritschel, W.A. Influence of obesity on sulfonamide disposition in Zucker rats. Eur. J. Drug Metab. Pharmacokinet. 13, 273–283 (1988). https://doi.org/10.1007/BF03190091
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03190091