Effects of furosemide on extravascular diffusion, protein binding and urinary excretion of cephalosporins and aminoglycosides in rabbits.

We studied the effects of furosemide on the disposition of cefazolin and gentamicin in rabbits. The following points were investigated: protein binding (PB) by ultracentrifugation in vitro; renal excretion and distribution in extravascular fluid (EF) obtained from s.c. tissue cages in vivo. Single i.m. injections of cefazolin (30 mg/kg) and gentamicin (1.5 mg/kg) alone or in combination with furosemide (0.5, 1 and 5 mg/kg) were made. After furosemide injection, blood and EF levels of gentamicin significantly decreased. Cefazolin blood levels were unchanged. Cefazolin appeared in EF earlier and at higher levels, up to 4 hr after furosemide injection, than when administered alone. Late cefazolin EF levels (8 and 12 hr) were reduced. All these effects were furosemide dose-dependent. Furosemide, in vitro, decreased cefazolin PG from 80 to 50%, whereas PB of gentamicin remained minimal (0--4%). Furosemide significantly increased the renal excretion of cefazolin and gentamicin without any effect on the glomerular filtration rate. A competitive effect of furosemide on the PB of cephradin and netilmicin was also demonstrated in vitro and in vivo. Our studies outline two kinds of interaction between furosemide and antibiotics. With protein-bound drugs, furosemide induced a competitive reduction of PB responsible for earlier EF diffusion and increased glomerular filtered load, but also induced an increased renal excretion by a tubular process. The latter was the only one induced by furosemide on unbound drugs (gentamicin).