Summary
Sulfadiazine (SDZ) 800 mg and trimethoprim (TMP) 160 mg were given orally to 10 normal subjects and the concentration of SDZ and TMP in serum and urine was followed for 24 h. Both drugs showed a significant negative correlation between individual “peak” concentrations in serum and the body weight of the subject. Twelve hours after dosing the serum concentration was 12 to 25 µg/ml for SDZ and 0.3 to 1.1 µg/ml for TMP. Individual concentration ratios between SDZ and TMP in serum were 4.8 (1 h) – 145 (24 h), and in the urine the ratio was close to 6 throughout the 24 h collection period. The range of urinary concentrations was from 65 to 400 µg/ml for SDZ and from 13.8 to 93.4 µg/ml for TMP. The fraction acetylated SDZ/acetylated SDZ + SDZ was 21% during the 0–8 h period, 33% during the 8–15 h period and 41% during the 15–24 period. The average values for the notional volume of distribution, Vd, were 0.36±0.13 1/kg for SDZ and 1.39±0.25 1/kg for TMP. The average “t1/2” was 15.2±7.4 h for SDZ and 7.4±1.9 h for TMP. Individual subjects showed a significant correlation between the serum clearance of TMP and SDZ (p<0.01) and also between the renal clearance of the two drugs (p<0.05). The serum clearance was significantly correlated with the renal clearance for TMP but not for SDZ. For SDZ Vd was significantly negatively correlated with the elimination constant; for TMP no such correlation was found. The serum clearance of SDZ was significantly correlated with the percentage of SDZ which was excreted as the (presumably) acetylated compound. The renal clearance of SDZ was independent of the serum concentration of SDZ. There was a highly significant negative correlation between the renal clearance and serum concentration of TMP, as well as for “acetylated SDZ”. The renal clearance of “acetylated SDZ” averaged more than six times that of unconjugated SDZ. With increased urine flow the renal clearances of TMP and SDZ were significantly increased.
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References
Acar, J. F., Goldstein, F., Chabbert, Y. A.: Synergistic activity of trimethoprim-sulfamethoxazole on gram-negative bacilli: Observations in vitro and in vivo. J. infect. Dis.128, S470-S477 (1973)
Bach, M. C., Finland, M., Gold, O., Wilcox, C.: Susceptibility of recently isolated pathogenic bacteria to trimethoprim and sulfamethoxazole separately and combined. J. infect. Dis.128, S508-S533 (1973a)
Bach, M. C., Gold, O., Finland, M.: Absorption and urinary excretion of trimethoprim, sulfamethoxazole, and trimethoprim-sulfamethoxazole. Results with single doses in normal young adults and preliminary observations during therapy with trimethoprim-sulfamethoxazole. J. infect. Dis.128, S584-S598 (1973b)
Bergan, T., Brodwall, E. K.: Kidney transport in man of sulfamethoxazole and trimethoprim. Chemotherapy17, 320–333 (1972)
Bergan, T., Vik-Mo, H., Ånstad, U.: Kinetics of a sulfadiazine-trimethoprim combination. Clin. Pharmacol. Ther.22, 211–224 (1977)
Bratton, A. C., Marshall, E. K. jr.: A new coupling component for sulfanilamide determination. J. biol. Chem.128, 537–550 (1939)
Brumfitt, W., Faiers, M. C., Pursell, R. E., Reeves, D. S., Turnbull, A. R.: Bacteriological, pharmacological and clinical studies with trimethoprim-sulphonamide combinations — with particular references to the treatment of urinary tract infections. Postgrad. med. J.45, 56–61 (1969)
Brumfitt, W., Hamilton-Miller, J. M. T., Kosmidis, J.: Trimethoprim-sulfamethoxazole: The present position. J. infect. Dis.128, S778-S791 (1973)
Bushby, S. R. M.: Trimethoprim-sulfamethoxazole: In vitro microbiological aspects. J. infect. Dis.128, S442-S462 (1973)
Craig, W. A., Kunin, C. M.: Distribution of trimethoprim-sulfamethaxazole in tissues of rhesus monkeys. J. infect. Dis.128, S575-S579 (1973)
Elsborg, L., Andreasen, F., Scherwin, J., Bülow, P.: Et nyt lavt doserbart trimethoprim-sulfonamid til langtidsbehandling af kronisk urinvejsinfektion. Ugeskr. Loeg.138, 735–738 (1976)
Kaplan, S. A., Weinfeld, R. E., Cotler, S., Abruzzo, C. W., Alexander, K.: Pharmacokinetic profile of trimethoprim in dog and man. J. Pharm. Sci.59, 358–363 (1970)
Kaplan, S. A., Weinfeld, R. E., Abruzzo, C. W., McFaden, K., Jack, M. L., Weissman, L.: Pharmacokinetic profile of trimethoprim-sulfamethoxazole in man. J. infect. Dis.128, S547-S555 (1973)
Männistö, P., Tuomisto, J., Saris, N-E., Lehtinen, T.: Pharmacokinetic studies with trimethoprim and different doses of sulfadiazine in healthy human subjects. Chemotherapy19, 289–298 (1973)
Nolte, H., Büttner, H.: Pharmacokinetics of trimethoprim and its combination with sulfamethoxazole in man after single and chronic oral administration. Chemotherapy18, 274–284 (1973)
Ohnhaus, E. E., Spring, P.: Elimination kinetics of sulfadiazine in patients with normal and impaired renal function. J. Pharmacokinet. Biopharm.3, 171–179 (1975)
Otten, H., Plempel, M., Wiegenthaler, W.: Antibiotika und Chemotherapeutika. Therapie mikrobieller Infektionen. Antibiotika-Fibel. Stuttgart: Georg Thieme Verlag 1975
Richterich, R.: Klinische Chemie, pp. 341–342. Basel: Karger 1971
Rieder, J.: Quantitative determination of the bacteriostatically active fraction of sulfonamides and the sum of their inactive metabolites in the body fluids. Chemotherapy17, 1–21 (1972)
Schwartz, D. E., Ziegler, W. H.: Assay and pharmacokinetics of trimethoprim in man and animals. Postgrad. med. J.45, 32–37 (1969)
Schwartz, D. E., Koechlin, B. A., Weinfeld, R. E.: Spectrofluorometric method for the determination of trimethoprim in body fluids. Chemotherapy14, 22–29 (1969)
Schwartz, D. E., Rieder, J.: Pharmacokinetics of sulfamethoxazole + trimethoprim in man and their distribution in the rat. Chemotherapy15, 337–355 (1970)
Seydel, J. K., Wempe, E., Miller, G. H., Miller, L.: Kinetics and mechanisms of action of trimethoprim and sulfonamides, alone or in combination, upon Escherichia coli. Chemotherapy17, 217–258 (1972)
Seydel, J. K., Wempe, E., Miller, G. H., Miller, L.: Quantification of the antibacterial action of trimethoprim alone and in combination with sulfonamides by bacterial growth kinetics. J. infect. Dis.128, S463-S469 (1973)
Sharpstone, P.: The renal handling of trimethoprim and sulphamethoxazole in man. Postgrad. med. J.45, 38–42 (1969)
Sigel, C. W., Grace, M. E., Nichol, C. A.: Metabolism of trimethroprim in man and measurement of a new metabolite: A new fluorescence assay. J. infect. Dis.128, S580-S583 (1973)
Tuomisto, J., Saris, N-E: Effective plasma and urine concentration of some sulfonamides and sulfonamide combinations. Ann. Med. exp. Fenn.48, 38–48 (1970)
Welling, P. G., Graig, W. A., Amidon, G. L., Kunin, C. M.: Pharmacokinetics of trimethoprim and sulfamethoxazole in normal subjects and in patients with renal failure. J. infect. Dis.128, S556-S566 (1973)
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Andreasen, F., Elsborg, L., Husted, S. et al. Pharmacokinetics of sulfadiazine and trimethoprim in man. Eur J Clin Pharmacol 14, 57–67 (1978). https://doi.org/10.1007/BF00560259
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DOI: https://doi.org/10.1007/BF00560259