The pharmacokinetics of a series of sulfonamides were investigated after intravenous administration of a 7 mg/kg dose of individual sulfonamides to cannulated female lean Zucker rats. The concentrations of the sulfonamides in blood were determined by colorimetry. The blood concentration-time curves were fitted to a biexponential equation. The partition coefficient, log P, and pKa values of the sulfonamides were taken from the literature, log P and pKa values differed markedly across the series. The extent of protein binding varied enormously, increasing with partition coefficient. There was no significant relationship between the volume of distribution and partition coefficient. However, when the influence of protein binding on volume of distribution was eliminated, a significant linear relationship emerged. Total clearance formed a relatively complex nonlinear relationship with partition coefficient. The relationship of elimination half-life and partition coefficient was inverwe of that between clearance and partition coefficient because of a lack of significant relationship between volume of distribution and partition coefficient.
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Seydel JK., Tretin D., Cordes HP. (1980) Quantitative structure-pharmacokinetic relationships derived on antibacterial sulfonamides in rats and its comparison to quantitative structure-activity relationships. J. Med. Chem., 23, 607–613.
Overton E. (1897): Uber die osmotischen Eigenschaften der Zelle in ihrer Bedeutung fur die Toxikologie und Pharmakologie. Z. Phys. Chem., 22, 189–209.
Meyer H. (1899): Zur Theorie der Alkoholnarkose. I. Welche Eigenschaft der Anasthetica beding ihre narkotische Wirkung? Arch. Exp. Pathol. Pharmakol., 42, 109–118.
Hansch C., Fujita T. (1964): η-σ-п analysis. A method for the correlation of biological activity and chemical structure. J. Am. Chem. Soc., 86, 1616–1626.
Purcell WP., Bass GE., Clayton JM. (1973): Strategy of Drug Design: A Molecular Guide to Biological Activity. New York, Wiley.
Hansch C. (1978): In Chapman NB, Shorter J. eds. Correlation Analysis in Chemistry: Recent Advances. New York, Plenum, pp. 397–438.
Martin YC. (1978): Quantitative Drug Design. New York, Marcell Dekker.
Seydel JK., Schaper K-J. (1979): Chemische Struktur und biologische Activitat von Wirkstoffen. Methoden der Quantitativen Struktur-Wirking Analyse. Weinheim, Verlag Chemie.
Miller GH., Doukas PH., Seydel JK. (1972): Sulfonamide structure activity relationships in a cell-free system. Correlation of inhibition of folate synthesis with antibacterial activity and physicochemical parameters. J. Med. Chem., 15, 700–706.
Seydel JK. (1981): Mode of action and quantitative-structure activity relationship of sulfonamides in biological systems of different complexity (enzymes, bacteria, rat and human). Int. J. Quant. Chem., 20, 131–150.
Ariens EJ., Simonis AM., Van Rossum JM. (1964): The relation between stimulus and effect. Mol. Pharmacol., 1, 394–466.
Belleau B. (1964): A molecular theory of drug action based on induced conformational perturbations of receptors. J. Med. Chem., 7, 776–784.
Levy G. (1966): Kinetics of pharmacological effects. Clin. Pharmacol. Ther., 7, 362–372.
Kruger-Thiemer E., Bunger P. (1965/66): The role of therapeutic regimen in dosage design. Chemotherapia, 10, 61–73, 129–144.
Toon S., Rowland M. (1979): Quantitative structure pharmacokinetic activity relationship with some tetracyclines. J. Pharm. Pharmacol., 31 (suppl.), 43P.
Toon S., Rowland M. (1983): Structure-pharmacokinetic relationships among the barbiturates in the rat. J. Pharmacol. Exp. Ther., 225, 752–763.
Bird AE., Marshall AC. (1967): Correlation of serum binding of penicillins with partition coefficients. Biochem. Pharmacol., 16, 2275–2290.
Morishita T., Yamazaki M., Yata, N., Kamada A. (1973): Studies on absorption of drugs. VIII. Physicochemical factors affecting the absorption of sulfonamides from rat small intestine. Chem. Pharm. Bull., 21, 2309–2322.
Lin Y-J., Awazu, S., Hanano M., Nogami H. (1973): Pharmacokinetic aspects of elimination from plasma and distribution to brain and liver of barbiturates in rats. Chem. Pharm. Bull., 21, 2749–2756.
Houston JB., Upshall DG., Bridges JW. (1975): Further studies using carbamate esters as model compounds to investigate the role of lipophilicity in the gastrointestinal absorption of foreign compounds. J. Pharmacol. Exp. Ther., 195, 67–72.
Ritschel WA., Hammer GV. (1980): Prediction of volume of distribution from in vitro data and use for estimating the absolute extent of absorption. Int J. Clin. Pharmacol. Ther. Toxicol., 18, 298–316.
Seydel JK. (1984): Quantitative structure-pharmacokinetic relationships and their importance in drug design, possibilities and limitations. Meth. Findings Exp. Clin. Pharmacol., 6, 571–581.
Watari N., Sugiyama Y., Kaneniwa, N., Hiura M. (1988): Prediction of hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit based on quantitative structure-pharmacokinetic relationships. J. Pharmacokinet. Biopharm., 16, 279–301.
Seydel JK., Schaper K-J. (1982): Quantitative-structure pharmacokinetic relationships and drug design. Pharmacol. Ther., 15, 131–182.
Anton AH., Boyle JJ. (1964): Alteration of the acetylation of sulfonamides by protein binding, sulfinpyrazone and suramin. Can. J. Physiol. Pharmacol., 42, 809–817.
Heel RC., Avery GS. (1980): In: Avery GS. ed. Drug Treatment. New York, Adis Press, pp. 1121–1124.
Leo A., Hansch C., Elkins D. (1971): Partition coefficients and their uses. Chem. Rev., 71, 525–616.
Kaul S., Ritschel WA. (1987): Free fatty acids and the binding of sulfonamides in the serum of genetically obese Zucker rat. Meth. Finding Expt. Clin. Pharmacol., 9, 317–320.
Kaul S., Ritschel WA. (1988): Influence of obesety on sulfonamide disposition in Zucker rats. Eur. J. Drug Metab. Pharmacokinet., 13, 273–283.
Bratton AC., Marshall, EK. Jr (1939): A new coupling component for sulfanilamide determination. J. Biol. Chem., 128, 537–550.
Metzler CM., Elfring GL., McEwan AJ. (1974): A package of computer programs for pharmacokinetic modeling. Biometrics, 30, 562–563.
Wagner JG. (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.
Craig WH., Welling PG. (1977): Protein binding of antimicrobials. Clinical pharmacokinetic and therapeutic implications. Clin. Pharmacokinet., 2, 252–268.
Brodie BB., Hogben AM. (1957): Some physicochemical factors in drug action. J. Pharm. Pharmacol., 9. 345–380.
Thorp JM. (1971): In: Buins TB. ed. Absorption and Distribution of Drugs. Edinburgh, Livingstone, pp. 64–76.
Ariens EJ. (1971): In: Ariens EJ. ed. Drug Design. New York, Academic Press, pp. 1–127.
Koizumi T., Arita T., Kekemi K. (1964): Absorption and excretion of drugs. XXI. Some pharmacokinetic aspects of absorption and excretion of sulfonamides. Chem. Pharm. Bull., 12, 428–432.
Gibaldi M., Koup JR. (1981): Pharmacokinetic concepts-drug binding, apparent volume of distribution and clearance. Eur. J. Clin. Pharmacol., 20, 299–305.
Notari RE. (1973): Pharmacokinetics and molecular modification: implications in drug design and evaluation. J. Pharm. Sci., 62, 865–881.
Struller T. (1968): In: Jucker E. ed. Progress in Drug Research, Vol. 22. Basel, Birkhauser, pp. 390–451.
Seydel JK., Miller G., Doukas PH. (1973): In: Pratesi P. ed. Medicinal Chemistry, London, Butterworths, pp. 139–151.
In memory of G. Ritschel, PhD — wife, mother, scientist and a friend
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Kaul, S., Ritschel, W.A. Quantitative structure — pharmacokinetic relationship of a series of sulfonamides in the rat. Eur. J. Drug Metab. Pharmacokinet. 15, 211–217 (1990). https://doi.org/10.1007/BF03190206
- structure-pharmacokinetic relationships