Effect of orally administered probenecid on the pharmacokinetics of cefoxitin

Abstract

To characterize the effects of orally administered probenecid on the phannacokinetics of cefoxitin in healthy male volunteers, we administered to one group of six subjects 2 g of cefoxitin by intravenous (i.v.) bolus either alone, with 1 g of probenecid concomitantly, or when 1 g of probenecid was administered 1 h previously by using a crossover design. Likewise, we administered to a second group of six subjects 2 g of cefoxitin intramuscularly (i.m.) Probenecid competitively inhibits the rena tubular secretion of other organic acids (20) anc has been used with penicillins and cephalospo rins to increase and sustain antibacterial concen trations to enhance therapeutic efficacy (3,8,11) Cefoxitin, a cephamycin derivative, is eliminatec primarily by glomerular filtration and tubulsi secretion (17). The purpose of the present stud) was to characterize the effect of probenecid or the blood and urine concentrations of intrave nously (i.v.) and intramuscularly (i.m.) admin istered cefoxitin. The portion of the study or i.v.-administered cefoxitin allowed a completE pharmacokinetic analysis ofthe effect of proben ecid on the disposition of cefoxitin. The portior on i.m.-administered cefoxitin allowed us to as sess the interaction under the conditions of comr mon clinical use (1).

Population pharmacokinetics of prophylactic cefoxitin in patients undergoing colorectal surgery

“…Residual drug clearance with the linear and nonlinear model was 90 and 20 mL/min, respectively. Taking into account that cefoxitin is primarily eliminated unchanged by renal excretion, with a 24-h urinary excretion of approximately 84% [29], a better estimation of the clearance in patients with a CL CR of <10 mL/ min was obtained with the nonlinear model than with the linear model. Table 3 lists the population PK parameters of cefoxitin in patients after intravenous infusion administration.…”

Competitive Inhibition of Renal Tubular Secretion of Gemifloxacin by Probenecid

“…The extent of interaction with probenecid may reach clinical significance for drugs which display active tubular secretion (12,21,33). Reduced renal clearance with probenecid has been reported for several quinolones, e.g., norfloxacin (25), fleroxacin (23), enoxacin (35), ciprofloxacin (14), levofloxacin (10,11), and gatifloxacin (21).…”

Pharmacokinetics of β-Lactam Antibiotics

“…Serum levels are proportional to dose over a dose range of 0.25-3 g. Multiple doses in this range given every 4 h do not cause accumulation of cefoxitin in healthy volunteers. The volume of distribution experienced by cefoxitin in the vascular compartment is approximately 8 liters (SIMON et al 1978 b;SONNEVILLE et al 1976;PAZIN et al 1979;SCHROGIE et al 1978SCHROGIE et al , 1979GOODWIN et al 1974;BRUMFITT et al 1974;BRISSON et al 1980;VLASSES et al 1980). Longer apparent serum half-lives were reported by CHRISTOPIDms et al (1978) in older patients with osteoarthritis.…”

“…HEKSTER et al (1980) noted similar occurrences. In a study by VLASSES et al (1980) it was shown that administering probenecid orally 60 min before an intravenous bolus dose of cefoxitin was given allowed the full effect of probenecid to be exerted. Renal clearance of cefoxitin was below 100 ml/min.…”