Trimethoprim pharmacokinetics

Erdmann, G.R. Canafax, D.M. Giebink, G.S. Hi -performance liquid chromatographic analysis of trimethoprim and sulfamethoxeizole in microUter volumes of chinchilla middle ear effusion and serum. J.Chromatogr., 1988, 433, 187-195 [LOQ 500 ng/mL LOD 250 ng/mL cimetidine (IS) column temp 45° extracted trimethoprim pharmacokinetics]... 

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). 

Table 46-1 Pharmacokinetic Properties of Some Sulfonamides and Trimethoprim ...

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. 

When a single dose of radiolabeled sulfadiazine was administered to eels at 7 C (200), highest initial radioactivity was observed in blood, liver, kidney, and skin, with a tendency for accumulation in bile and skin. In another pharmacokinetic study (201) on sea-water rainbow trout fed a combination of sulfadia-zine-trimetlroprim, the elimination process for both sulfadiazine and trimethoprim rapidly reached a point at which only a small but persistent residue was left at 8 C as opposed to 10 C, sulfadiazine was the more potent residue promoter, still being detected at 90 days posttreatment. This was suggested to be a result of the greater binding ability of sulfadiazine as a weak electrolyte. The authors proposed a witlidrawal period for sulfadiazine-trimethoprim of 60 days at water temperatures above 10 C for tabled-size fish, and a prohibition on its use below 10 C for such fish. 

Apart from the pathophysiological condition of the animal, the mode of drug application may also significantly influence the pharmacokinetic profile of a drug (48, 49). For example, drug residues may persist at the injection site for prolonged periods of time (2). In a study in which various sulfonamides and trimethoprim were injected intramuscularly into swine, detectable residues were found at most sites 6 days after the injection, and with the sulfonamides at 30 days in almost half of the animals (50). Other drugs such as dihydrostreptomycin persist for up to 60 days, while positive residues of chloramphenicol are found at 7 days postinjection. Sodium and procaine penicillin, neomycin, tylosin, and oxytetracycline residues have also been determined at 24 h or more postinjection (51). 

Niemi M, Backman JT, Neuvonen PJ. Effects of trimethoprim and rifampicin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone. Clin Pharmacol Ther 2004 76 239 19. 

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. 

Note. For a review of the clinical pharmacokinetics of sulphamethoxazole and trimethoprim see R. B. Patel and P. G. Welling, Clin. Pharmacokinet., 1980,5,405-423. 

Jung D, AbdelHameed MH, Hunter J, Teitelbaum P, Dorr A, Griffy K. The pharmacokinetics and safety profile of oral ganciclovir in combination with trimethoprim in HIV- and CMV-seropositive patients. Br J Clin Pharmacol 1999 47(3) 255-9. 

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). 

In one pharmacokinetic study in eight HIV-infected subjects, the renal clearance of zidovudine was significantly reduced by trimethoprim (201). The authors concluded that zidovudine dosages may need to be reduced if trimethoprim is given to patients with impairment of liver function or glucuronidation. Zidovudine, on the other hand, did not alter the pharmacokinetics of trimethoprim. 

Garg SK, Ghosh SS, Mathur VS. Comparative pharmacokinetic study of four different sulfonamides in combination with trimethoprim in human volunteers. Int J Clin Pharmacol Ther Toxicol 1986 24(l) 23-5. 

Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS. Trimethoprim a review of its antibacterial activity, pharmacokinetics and therapeutic use in urinary tract infections. Drugs 1982 23(6) 405-30. 

Lee BL, Safrin S, Makrides V, Gambertogho JG. Zidovudine, trimethoprim, and dapsone pharmacokinetic interactions in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother 1996 40(5) 1231-6. 

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. 

Shoaf S E. Schwark W S, Guard C L 1989 Pharmacokinetics of sulfadiazine/trimethoprim in neonatal male calves effect of age and penetration into cerebrospinal fluid. American Journal of Veterinary Research 50 396-402 Taylor W M, Simpson C F, Martin F G 1972 Certain aspects of toxicity of an amicarbalide formulation to ponies. American Journal of Veterinary Research 33 533-541 Watkins W M, Mosobo M 1993 Treatment of Plasmodium falciparium malaria with pyrimethamine and sulphadoxine a selective pressure for resistance is a function of long elimination half-life. Transactions of the Royal Society of Tropical Medicine and Hygiene 87 75-79... 

Nouws, J.F.M., van Ginneken, V.J.T., Grondel, J.L. Degen, M. (1993) Pharmacokinetics of sulphadiazine and trimethoprim in carp (Cyprinus carpio L.) acclimated at two different temperatures. Journal of Veterinary Pharmacology and Therapeutics, 16, 110-113. 

Ladefoged, O. (1979) Pharmacokinetics of antipyrine and trimethoprim in pigs with endotoxin-induced fever. Journal of Veterinary Pharmacology and Therapeutics, 2, 209-214. 

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. 

Tagawa, Y., Kokue, E., Shimoda, M. Son, D. (1994) ai-Acid glycoprotein-binding as a factor in age-related changes in the pharmacokinetics of trimethoprim in piglets. 

Antibiotics that require TDM include aminoglycosides, chloramphenicol, sulfonamides, vancomycin, trimethoprim, P-lactams, and tetracyclines. Pharmacokinetic details of these antibiotics are summarized in Table 33-4. Aminoglycosides and vancomycin are quantified by immmioassay. Other antibiotics have been measured by HPLC. 

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