PHARMACOKINETICS OF BRODIMOPRIM

Brodimoprim is a dihydrofolate reductase inhibitor which is highly active against a broad spectrum of gram-negative and gram-positive bacteria. Single dose pharmacokinetics and dose proportionality of this drug were studied in healthy volunteers who received orally 150, 400 and 600 mg. Multiple dose pharmacokinetics were evaluated after administration of an oral loading dose of 400 mg followed by daily maintenance doses (tau = 24 h) of 200 mg on seven consecutive days. Plasma and urine samples were collected up to 4 days after dosing and analyzed for unchanged drug by an HPLC-assay with fluorescence detection. Approximately 4 hours after single oral administration of 150, 400 and 600 mg, C-max-values of 1.5, 3.3 and 6.2 mg/l were observed. The corresponding AUC-values after these doses were 73, 156 and 290 mg . h/l, respectively, and reflect a good dose proportionality in the investigated range. In the postdistributive phase an elimination half-life of 32-35 h was determined which justifies once-daily administration. Total plasma clearance (Cl-s/F) similar to 40 ml/min and renal clearance was similar to 3 ml/min. Approximately 80% of the dose was recovered from urine, but only 4-7% could be identified as unchanged drug. With faeces less than 10% of the dose was excreted predominantly as parent drug. Hence, metabolic degradation is the dominant elimination process of brodimoprim. The apparent volume of distribution (V-beta/F) was high (similar to 1.5 l/kg) and reflects the good penetration of brodimoprim into most body fluids and tissues. During multiple dosing, the pharmacokinetic parameters of brodimoprim remained unchanged, and induction or inhibition of the drug metabolizing/eliminating enzymes can be excluded. At steady state, drug accumulation in plasma reached a factor of 2.6 and therefore a reduction of the maintenance dose by 50% is recommended.