Nephrotoxic and peroxidative potential of meropenem and imipenem/cilastatin in rat and human renal cortical slices and microsomes

Background: Carbapenems are a relatively new class of beta-lactam antibioti cs characterized by a broad spectrum of antibacterial activity. Meropenem ( MER), a new carbapenem has shown a lower nephrotoxic potential compared to imipenem (IMI). IMI is used in a fixed one-to-one combination with the neph roprotective agent cilastatin (Cn). The present studies examined whether ME R and IMI/CIL produce peroxidative and nephrotoxic alterations including ox idative changes in rat and human renal cortical slices and microsomes. Mate rials and methods:Untreated slices and microsomes were incubated in vitro f or various periods of time in phosphate-buffered media containing various c oncentrations of MER, IMI/CIL or for comparison cephaloridine (CPH). Lipid peroxidation was monitored by the determination of malondialdehyde (MDA) in incubation media and slices in the presence or absence of antioxidants. To tal glutathione, oxidized glutathione (GSSG), pyruvate-stimulated gluconeog enesis and paraaminohippurate (PAH) accumulation were measured in slices. R esults: In rat renal cortical slices, MER, IMI/CIL and CPH induced a time- and concentration-dependent MDA production (content in incubation media plu s slices). 5 mM MER, 5 mM IMI/CIL and 3 mM CPH were the lowest concentratio ns which caused a significant MDA production after 3 hs compared to control (control 61.5 +/- 15.3 nmol MDA/g tissue, MER 75.4 +/- 10.9, p < 0.001; co ntrol 48.0 +/- 8.7, IMI/CIL 65.1 +/- 11.7, p < 0:001; control 61.5 +/- 15.3 , CPH 113.0 +/- 28.2, p < 0.001). 20 mM MER, 20 mM IMI/CLL and 12 mM CPH re vealed marked MDA production after 3 hs in human renal cortical slices (con trol 29.8 +/- 4.2 nmol MDA/g tissue, MER 49.4 +/- 8.7, p < 0.01; control 27 .6 +/- 7.0, IMI/CLL 68.3 +/- 9.9, p < 0.001; control 32.5 +/- 7.7, CPH 93.8 +/- 31.6, p < 0.001) and in human renal microsomes (control 1.0 +/- 0.9 nm ol MDA/mg protein, MER 2.9 +/- 1.0, p < 0.05; IMI/CIL 6.8 +/- 2.2, p < 0.00 1; CPH 8.4 +/- 2.2, p < 0.001), respectively. The corresponding MDA product ion was about 2-fold higher in rat renal cortical slices and almost the sam e in rat renal microsomes. Antioxidants reduced the MER-induced increase in MDA content in rat renal cortical slices by 48% (alpha-tocopherol, 10(-4) M), 72% ((+)-cyanidanol-3, 10(-5) M) and 100% (DPPD, N,N'-diphenyl-p-phenyl endiamine, 10(-6) M). In rat renal cortical slices, MER and IMI/CIL induced an increase up to 50% in the content of GSSG and a corresponding %-decreas e in reduced glutathione (GSH). In rat renal cortical slices, MER and IMI/C IL induced a time- and concentration-dependent decrease in PAH accumulation and gluconeogenesis. PAH accumulation was already reduced by 5 mM MER afte r 1 h (control slice to medium ratio 18.3 +/- 6.8, MER 10.7 +/- 1.9, p < 0. 05) and by 10 mM IMI/CIL after 3 h (control 16.9 +/- 5.6, IMI/CIL 5.5 +/- 1 .3, p < 0.001). Pyruvate-stimulated gluconeogenesis after 3 hs was already reduced by 2.5 mM MER (control 5.7 +/- 2.1 mu mol glucose/g tissue/h, MER 3 .9 +/- 1.1, p < 0.05) and by 10 mM IMI/CLL (control 5.7 +/- 2.1, IMI/CIL 2. 8 +/- 1.0, p < 0.001). Conclusion: Thus, MER and IMI/CLL (at concentrations more than 10-fold higher as peak plasma concentrations achieved in humans) revealed an oxidative change (depletion of GSH, production of GSSG), a per oxidative potential (production of MDA) and a nephrotoxic potential (reduct ion in pyruvate-stimulated gluconeogenesis and PAH accumulation). Human kid ney seems to be less susceptible to beta-lactam antibiotic-induced lipid pe roxidation than rat kidney.