Steady state pharmacokinetics of trimethoprim 300 mg once daily in healthy volunteers assessed by two independent methods.

The steady state pharmacokinetics of trimethoprim was determined after 300 mg orally once daily to 6 healthy volunteers for 9 days. The microbiological assay of plasma level was unreliable at trimethoprim concentrations greater than 4 micrograms/ml, so results from an HPLC-assay are given. Steady state was present after 3 days. The plasma concentration peaked 1 to 4 h (mean 2.0 h) after the dose at a mean of 6.0 micrograms/ml (range 3.1-9.5 micrograms/ml); the minimum value was 1.5 micrograms/ml (range 0.6-2.9 micrograms/ml). The mean AUCss was 77 micrograms/ml X h and the mean plasma clearances was 67 and 74 ml/min on Days 8 and 9. Renal clearance was about 60% of the plasma clearance. The average plasma half life was 10.6 h (range 8.7-15.3 h). Thus, there was considerable interindividual variation in all pharmacokinetic parameters. 72 h after the last dose trimethoprim was detectable in plasma in only 1 of the 6 subjects. The minimum urinary concentration of trimethoprim during treatment was always well above (range 22 to 220 micrograms/ml) the MIC values for most urinary tract pathogens. Therefore, a daily dose of 300 mg trimethoprim results in a therapeutic concentration in urine at steady state that lasts throughout the dosing interval and in most subjects probably lasts also for a further 24 h. Trimethoprim administration raised mean serum creatinine from 67 to 97 mumol/l, probably due to competitive inhibition of the tubular secretion of creatinine.