Trimethoprim distribution

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). 

Trimethoprim is usually given orally, alone, or in combination with sulfamethoxazole, which has a similar half-life. Trimethoprim-sulfamethoxazole can also be given intravenously. Trimethoprim is well absorbed from the gut and distributed widely in body fluids and tissues, including cerebrospinal fluid. Because trimethoprim is more lipid-soluble than sulfamethoxazole, it has a larger volume of distribution than the latter drug. 

Baquiloprim has a high oral bioavailability in animals where it is widely distributed in the body and slowly eliminated (222,223). In cattle, baquiloprim was reported to have a much longer half-life and a larger volume of distribution than trimethoprim (223). Both urine and bile are important routes of elimination. 

In all target species, trimethoprim is rapidly and almost completely absorbed, and widely distributed throughout the body after oral administration. A significant proportion of the residues in tissues consists of unmetabolized trimethoprim, but several metabolites including the 1-A-oxide, 3-A-oxide, 3-hydroxy, 4-hydroxy, and the -hydroxy metabolites are also present, each metabolite comprising less than 5% of the total residues. 

Administration and metabolism Trimethoprim is more lipid-soluble than sulfamethoxazole and has a greater volume of distribution. Administration of 1 part of trimethoprim to 5 parts of the sulfa drug produces a ratio of the drugs in the plasma of 20 parts of sulfamethoxazole to 1 part trimethoprim. This ratio is optimal for the antibiotic effect. Co-trimoxazole is generally administered orally. An exception involves intravenous administration to patients with severe pneumonia caused by Pneumocystis carinii. or to patients who cannot take the drug by mouth. 

Fate Both agents distribute throughout the body. Trimethoprim concentrates in the relatively acidic milieu of prostatic and vaginal fluids and accounts for the use of the trimethoprim-sulfamethoxazole combination in infections at these sites. Both parent drugs and their metabolites are excreted in the urine. 

In humans, serum creatinine is dependent on non renal factors independent of kidney function e.g. muscle mass, nutritional status, infection, volume of distribution. Also, serum creatinine is dependent on renal factors that are independent of function. For example, certain drugs like trimethoprim and cimetidine elevations in serum creatinine by altering the normal elimination pathways of creatinine. In addition, in humans, alterations in serum creatinine may lag several days behind actual changes in GFR. Earher detection of AKI with a kidney specific biomarker may be essential for early and successful treatment of AKI in humans. 

Craig WA, Kunin CM. Distribution of trimethoprim-sulfamethoxazole in tissues of rhesus monkeys. The Journal of infectious diseases. 1973 Nov l 28 Suppl 575-9 p. 

Sulfonamides are weak acids. They distribute well but relatively slowly (compared with trimethoprim), and tissue concentrations are lower than plasma concentrations. Some sulfonamides reach significant concentrations in the CSF. The highest drug concentrations are in the liver, kidneys and lungs lower levels are achieved in muscle and bone. Sulfonamides cross the placenta and some may achieve therapeutic concentrations in milk. Some are highly protein bound protein binding varies with both the species and the drug. The Vj values in horses for sulfamethazine, sulfadox-ine and sulfadiazine are 0.63, 0.39 and 0.581/kg, respectively. 

The effect of experimentally induced bacterial infections, all of which have in common the presence of fever, on the disposition of various antimicrobial agents in pigs is presented in Table 3.1. In the infected pigs, the apparent volume of distribution of penicillin G, ampicillin and, to a lesser extent, trimethoprim is increased, of enrofloxacin and sulphonamides remains unchanged, and of oxytetracycline is decreased. The systemic clearance of penicillin G, ampicillin and trimethoprim is increased, of sulphamethoxazole and sulphadimethoxine remains unchanged, and of sulphadimidine,... 

Trottier S, Bergeron MG, Lessard C. Intrarenal distribution of trimethoprim and sulfa-methoxazole. Antimicrob Agents Chemother 1980 17 383-388. 

Following oral administration, lamivudine is absorbed rapidly with a bioavailability of about 80% in adults. Peak plasma levels average approximately 1000 ng/mL after 100-mg doses. Lamivudine is distributed widely in a volume comparable with total-body water. The plasma t,/2 of elimination averages about 9 hours, and approximately 70% of the dose is excreted unchanged in the urine. About 1% is metabolized to an inactive trawY-sulfoxide metabolite. In HBV-infected children, doses of 3 mg/kg per day provide plasma exposure and trough plasma levels comparable with those in adults receiving 100 mg daily. Dose reductions are indicated for moderate renal insufficiency (creatinine clearance <50 ml/min). Trimethoprim decreases the renal clearance of lamivudine. 

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. 

Trimethoprim is distributed and concentrated rapidly in tissues, and 40% is bound to plasma protein in the presence of sulfamethoxazole. The volume of distribution of trimethoprim is almost nine times that of sulfamethoxazole. The drug readily enters CSF and sputum. High concentrations of each component also are found in bUe. About 65% of sulfamethoxazole is bound to plasma protein. 

Managaki S, Murata A, Takada H, Tuyen BC, Chiem NH (2007) Distribution of macrolides, sulfonamides, and trimethoprim in tropical waters Ubiquitous occurrence of veterinary antibiotics in the Mekong Delta. Environ Sci Technol 41 8004-8010... 

Sulphamethoxazole ( Gantanol 3-p-aminobenzenesulphonamido-5-me-thylisoxazole) has been selected for use with trimethoprim for sequential blocking (Section 9.5), because both drugs have similar distribution and duration. 

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