Pharmacokinetics of Methioprim in Human Volunteers

Abstract

The pharmacokinetics of methioprim have been studied in 11 healthy volunteers who received tablets of 320 mg as a first dose followed by 160 mg every 12 h. The concentrations were measured in plasma and skin blisters formed by suction, by high-pressure liquid chromatography. The mean individual peak concentrations during approximate steady state on the fourth day were 2.7 mg/l in serum and 1.3 mg/l in blister fluid. At steady state, 7.1 % of the dose was recovered in urine during the dosage interval of 12 h. The plasma half-life was the same after the first and final, steady state, dose with means ( ± SD) 9.29 ± 3.51 and 9.34 ± 2.19 h (NS). The substance was rapidly absorbed from the intestines with a rate constant of 2.345 ± 0.688 ^h––¹. The rate constant of invasion into blister fluid after the first dose was 0.801 ± 0.164 ^h––1. The apparent lag time before gastrointestinal absorption was 0.29 h and before appearance in the blisters 1.23 h. The 12-hour area under the blister fluid curve was 39% of the plasma curve area after the first dose and 59% during steady state. The respective values for the time versus concentration curve until infinity were 63 and 99%.

Pharmacokinetics of Brodimoprim in Serum and Skin Blister Fluid

“…Elimination of brodimoprim was slower than reported for other dihydrofo late reductase inhibitors like trimethoprim [2,11,12] and methioprim [13]. The pres ent ti/2 of brodimoprim was approxi mately 3 times that of trimethoprim in pre vious studies [3,14], Contributing to the longer t|/2 of brodimoprim is a higher pro tein binding (89% for brodimoprim vs. 45% for trimethoprim) [14], The slightly lower affinity of brodimoprim to the hu man dihydrofolate reductase affinity tends in the opposite direction.…”

“…The pres ent ti/2 of brodimoprim was approxi mately 3 times that of trimethoprim in pre vious studies [3,14], Contributing to the longer t|/2 of brodimoprim is a higher pro tein binding (89% for brodimoprim vs. 45% for trimethoprim) [14], The slightly lower affinity of brodimoprim to the hu man dihydrofolate reductase affinity tends in the opposite direction. As a conse quence of the slow elimination, therapeu tic brodimoprim concentrations were maintained for more than 24 h, and even after 48 h the concentrations exceeded the minimum inhibitory concentrations (MICs) of several pathogenic bacteria [1], Penetration to blister fluid was marked; the invasion rate corresponded to a dou bling time of 2.6 h, which is 3 times above that of methioprim found in a similar suc tion blister model [13]. The peak concen tration in blister fluid being approxi mately 1/3 of the peak in serum, and an AUCbiister of 73% of the AUCserum also exceeded the values for methioprim.…”

Pharmacokinetics and Metabolism of Metioprim in Pigs and Goats

“…The metabolism of MTP in the two animal species is also more extensive than in man who excretes 20-27% unchanged MTP in urine after intravenous administration of a single dose (Plozza-Nottebrock et al 1981). From a study with oral administration of MTP to human volunteers Bruun et al (1983), however, reported that only 7% of the dose was excreted as unchanged drug under steady state conditions. The major metabolite of MTP in urine from both pigs and goats was found to be metioprim sulfoxide.…”

“…198 1). Clinical investigations in man have shown MTP to have a longer half-life than TMP -10 hrs versus 7 hrs (Andreasen et al 1978;Bishop-Freudling & Vergin 1981;Plozza-Nottebrock et al 1981;Bruun et al 1983). In domestic animals TMP is eliminated much faster than in man (Baggot 1982), and also much faster than the sulfonamides in combination with which it is used in veterinary practice (Nielsen & Rasmussen 1976).…”