Sulfamethoxazole, pharmacokinetics

Kaolin-pectin can cause a small but probably clinically unimportant reduction in serum trimethoprim levels, and has no effect on sulfamethoxazole pharmacokinetics. 

Co-trimoxazole suspension (trimethoprim 160 mg with sulfamethoxazole 800 mg) was given to 8 healthy subjects, with and without 20 mL of kaolin-pectin suspension. The kaolin-pectin reduced the AUC and the maximum serum levels of the trimethoprim by about 12% and 20%, respectively. Changes in the sulfamethoxazole pharmacokinetics were not significant. The probable reason for this reduction in AUC is that trimethoprim is adsorbed onto the kaolin-pectin, which reduces the amount available for absorption. However, the reductions are small and unlikely to be clinically relevant. 

Pharmacokinetics Rapidly and well absorbed from the GI tract. Protein binding 45%-60%. Widely distributed. Metabolized in the liver. Excreted in urine. Minimally removed by hemodialysis. Half-life sulfamethoxazole 6-12 hr, trimethoprim 8-10 hr (increased in impaired renal function). 

Many antimicrobial agents have similar pharmacokinetic properties when given orally or parenterally (ie, tetracyclines, trimethoprim-sulfamethoxazole, quinolones, chloramphenicol, metronidazole, clindamycin, rifampin, linezolid and fluconazole). In most cases, oral therapy with these drugs is equally effective, is less costly, and results in fewer complications than parenteral therapy. 

The pharmacokinetic characteristics of trimethoprim are similar to sulfamethoxazole, but higher concentrations are achieved in the relatively acidic prostatic and vaginal fluids since it is a weak base. Trimethoprim undergoes O-demethylation. 

Trimethoprim is most often compounded with the sulfa drug, sulfamethoxazole. The resulting combination, called co-trimoxazole, shows greater antimicrobial activity than equivalent quantities of either drug used alone (Figure 29.6). The combination was selected because of the similarity in the pharmacokinetics of the two drugs. 

A widely available fixed combination is co-trimoxazole (Bactrim, Eusaprim, Septrin), which contains trimethoprim and sulfamethoxazole in a ratio of 1 5. Both trimethoprim and sulfamethoxazole have favorable and comparable pharmacokinetics and the combination is bactericidal (4). Synergy between trimethoprim and sulfonamides has conventionally been ascribed to sequential inhibition of dihydropteroate synthetase by sulfonamides (in competition with pora-aminobenzoic acid) and of dihydrofolate reductase by trimethoprim (in competition with dihydrofolate). However, sulfonamides in high concentrations also inhibit dihydrofolate reductase. Thus, an initial partial sequential blockade by trimethoprim (inhibition of dihydrofolate reductase) and sulfonamides (inhibition of dihydropteroate synthetase) leads to defective protein synthesis and cytoplasmic damage, which in turn results in marked increases in the uptake of both agents and double strength inhibition of dihydrofolate reductase (5). 

Siber GR, Gorham CC, Ericson JF, Smith AL. Pharmacokinetics of intravenous trimethoprim-sulfamethoxazole in children and adults with normal and impaired renal function. Reviews of infectious diseases. 1982 Mar-Apr 4(2) 566-78. 

Nissenson AR, Wilson C, Flolazo A. Pharmacokinetics of intravenous trimethoprim-sulfamethoxazole during hemodialysis. American journal of nephrology. 1987 7(4) 270-4. 

Mengelers, M.J.B., van Gogh, E.R., Kuiper, H.A. et al. (1995) Pharmacokinetics of sul-fadimethoxine and sulfamethoxazole in combination with trimethoprim after intravenous administration to healthy and pneumonic pigs. Journal of Veterinary Pharmacology and Therapeutics, 18, 243-253. 

The renal clearance of sulfamethoxazole, but not of its metabolite, Nij-acetylsulfamethoxazole, was markedly influenced by urinary pH and urine flow. Pharmacokinetic analysis of percutaneous absorption showed evidence of parallel penetration pathways for methotrexate when it was topically applied to hairless mouse skin. ... 

Brown, M.P. Gronwall, R. Castro, L. Pharmacokinetics and body fluid and endometrial concentrations of trimethoprim-sulfamethoxazole in mares. Am.J.Vet.Res., 1988, 49, 918-922... 

Mengelers, M.J.B. Oorsprong, M.B.M. Kuiper, H.A. Aerts, M.M..L. Van Gogh, E.R. Van Miert, A.S.J.P.A.M. Determination of sulfadimethoxine, sulfamethoxazole, trimethoprim and their main metabolites in porcine plasma by column switching HPLC. J.Pharm.Biomed.Anal., 1989, 7, 1765-1776 Tu, Y.-H. Allen, L.V., Jr. Fiorica, V.M. Albers, D.D. Pharmacokinetics of trimethoprim in the rat. J.Pharm.ScL, 1989, 78, 556-560 [plasma brain heart lung liver spleen kidney prostate testicles seminal vesicles LOD 100 ng/mL chlorphenesin carbamate pharmacokinetics]... 

Spreux-Varoquaux, O. Chapalain, J.P. Cordonnier, P. Advenier, C. Pays, M. Lamine, L. Determination of trimethoprim, sulfamethoxazole and its N4-acetyl metabolite in biological fluids by high-performance liquid chromatography. J.Chromatogr., 1983, 274, 187-199 [LOD 15 ng/mL plasma urine normal phase gradient simultaneous theophylline non-interfering caffeine pharmacokinetics]... 

ABSORPTION, DISTRIBUTION, AND EXCRETION The pharmacokinetic profiles of sulfamethoxazole and trimethoprim are closely but not perfectly matched to achieve a constant ratio of 20 1 in their concentrations in blood and tissues. The ratio in blood is often greater than 20 1, while that in tissues is frequently less. After a single oral dose of the combined preparation, peak blood concentrations of trimethoprim usually occur by 2 hours, whereas peak concentrations of sulfamethoxazole require 4 hours. The half-lives of trimethoprim and sulfamethoxazole are 11 and 10 hours, respectively. 

Pairing these two particular antibacterial agents was based on pharmacokinetic factors and convenient availability. For such a combination to be useful in vivo, the two agents must arrive at the necessary tissue compartment where the infection Is at the correct time and in the correct ratio. In this context, the optimum ratio of these two agents in vitro Is 1 20. Of all the combinations tried, sulfamethoxazole came closest to being optimal for trimethoprim. Administration of a 1 5 combination of the two drugs orally produces the desired 1 20 ratio in the body once steady state is reached. Conveniently, sulfamethoxazole was already on the market, so it did not have to be approved specially by the U.S. Food and Drug Administration (FDA) for this purpose. 

A study in 12 healthy subjects given co-trimoxazole (trimethoprim and sulfamethoxazole) 9 mg daily for 7 days found that a single 1.2-g dose of azithromycin given on day 7 did not alter the pharmacokinetics of either trimethoprim or sulfamethoxazole to a clinically relevant extent. ... 

In a placebo-controlled study, 6 healthy subjects were given cimetidine 400 mg every 6 hours for 6 days, with a single 960-mg dose of co-trimox-azole (trimethoprim with sulfamethoxazole) on day 6. Although trimethoprim levels were consistently slightly higher in the presence of cimetidine, they were not significantly different. Cimetidine had no effect on the pharmacokinetics sulfamethoxazole. ... 

The pharmacokinetics of trimethoprim are not significantly affected by rifabutin, and probably not by rifampicin (rifampin). Rifabutin does not affect the pharmacokinetics of sulfamethoxazole, but significantly increases exposure to its hydroxylamine metabolite and as a result may increase adverse reactions to sulfamethoxazole in HIV-positive patients. 

Lee BL, Lampiris H, Colbom DC, Lewis RC, Narang PK, Sullam P The effect of rifabutin (RBT) on the pharmacokinetics (PK) of trimethoprim-sulfamethoxazole (TMP-SMX) in HIV-infected patients Intersci Ccmf Antimicrob Agents Chemoffier (1995) 35, 7... 

In 6 healthy subjects, oral salbutamol 4 mg four times daily for 2 weeks had no elTect on the pharmacokinetics of a single 400-mg oral dose of sulfamethoxazole (in co-trimoxazole), although the absorption rate constant was reduced by about 40% and the extent of absorption over 72 hours was increased by 22.6%. A possible reason for these effects is that salbutamol stimulates the beta receptors in the gut, causing relaxation, which allows an increased contact time, and therefore increased absorption of sulfamethoxazole. The clinical significance of this interaction is unknown, but it... 

Amsden GW, Foulds G, Thakker K. Pharmacokinetic study of azithromycin with fluconazole and cotrimoxazole (trimethoprim-sulfamethoxazole) in healthy volunteers. Clin Drug Invest... 

Altered (usually enhanced) coumarin response has been reported with virtually every class of antibacteriaL While some such as sulfamethoxazole, clearly have a pharmacokinetic interaction, for others there is no clear explanation for why an interaction might be expected. Theoretical mechanisms include reduced intestinal bacterial production of vitamin K2 substances, or reduced enter-ohepatic recycling. Possible confounding mechanisms include a reduction in dietary vitamin Kj intake because of illness, or the effect of fever or infection on coagulation or drug metabolism. 

Reduced or increased metabolism. Sulfamethoxazole clearly inhibits the metabolism of warfarin by the cytochrome P450 isoenzyme CYP2C9, so enhancing its effect. Some macrolides such as erythromycin inhibit CYP3A4, and therefore have a minor inhibitory effect on warfarin, which would, on its own, be unlikely to be of any clinical relevance. Conversely, rifamycins , (p.375) are well established inducers of drug metabolism, and clearly reduce the effect of warfarin. Most other antibacterial classes have no effect on warfarin pharmacokinetics. 

Co-trimoxazoie (Trimethoprim/Sulfamethoxazole). The manufacturers note that there was no pharmacokinetic interaction between adefovir 10 mg once daily and co-trimoxazole 960 mg twice daily in 18 heallhy subjects. ... 

Cidofovir with probenecid modestly decreased levels of trimethoprim and sulfamethoxazole (co-trimoxazole), and caused moderate increases in didanosine levels, but did not alter fluconazole pharmacokinetics. None of these drugs altered cidofovir pharmacokinetics. 

In a study, 6 HIV-positive subjects were given co-trimoxazole 960 mg daily with a single 3-mg/kg dose of cidofovir with probenecid given on day 7. The AUC and maximum plasma concentrations of both trimethoprim and sulfamethoxazole were decreased by about 30% and renal clearance was significantly increased. The pharmacokinetics of cidofovir were not affected. ... 

Co-trimoxazole (sulfamethoxazole/trimethoprim 800/160 mg) twice daily had no clinically relevant effect on the pharmacokinetics of maraviroc 300 mg twice daily (a 10% increase in AUC and a 19% increase in maximum level). ... 

In a study of 14 HIV-positive patients taking co-trimoxazole 960 mg daily for 5 days, it was found that the AUC of a single 300-mg dose of lamivudine given on day 4 was increased by 43% and the renal clearance was decreased by 35%. The pharmacokinetics of the trimethoprim and the sulfamethoxazole were unaffected. Similarly, in a population pharmacokinetic analysis, the concurrent use of lamivudine and co-trimoxazole was associated with a 31% reduction in the apparent oral clearance of lamivudine, and an estimated 43% increase in steady-state lamivudine levels. The UK manufacturer notes that the interaction is due to trimethoprim, and that sulfamethoxazole did not interact. ... 

Moore KHP, Yuen GJ, Raasch RH, Eron JJ, Martin D, Mydlow PK, Hussey EK. Pharmacokinetics of lamivudine administer alcme and with trimethoiirim-sulfamethoxazole. Clin Pharmacol Ther 996) 59,550-8. 

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