I. INTRODUCTION 



in avian liver and mammalian liver, lung, small 

 intestine, kidney, and gastrointestinal contents, 

 which may result in cytotoxicity and localized 

 injury in vivo to cellular membranes (Mason and 

 Holtzman, 1975a; Biaglow et al., 1977; Aufrere 

 et al., 1978; Boyd et al., 1979a; Sasame and 

 Boyd, 1979; Leskovac and Popovic, 1980; Peter- 

 son et al., 1982a) and to microbial organisms 

 (Hassan and Fridovich, 1979). Using rat (age, 

 sex, and strain unspecified) lung explants treat- 

 ed in culture with 10 3 M nitrofurantoin, Mar- 

 tin (1983) found significant lung cell injury, 

 which was increased with increased oxygen ten- 

 sion and decreased in the presence of superoxide 

 dismutase, catalase, a-tocopherol, and other an- 

 tioxidants. Rose et al (1982) reported that 100 

 mg/kg nitrofurantoin administered intraperito- 

 neally to rats (Wistar, age and sex not reported) 

 for 7 consecutive days caused changes in (5-glu- 

 curonidase and P-galactosidase activity in nerve 

 homogcnates, which indicated significantly in 

 creased enzyme activity and nerve degeneration. 



Under anaerobic conditions, lung and liver mi- 

 crosomal and soluble fractions (male, HLA-SD, 

 150 g) mediated the covalent binding of ["C|ni- 

 trofurantoin-derived radioactivity to acid-pre- 

 cipitated macromolecules (Boyd et al., 1979a). 

 Covalent binding of ["Cjnitrofurantoin activity 

 was greatest in the kidney, liver, ileum, lung, 

 and heart of rats. Reduced glutathione was re- 

 ported to decrease covalent binding of ['^Cjnitro- 

 furantoin-derived radioactivity. Olive and 

 McCalla (1977) reported that nitrofurantoin, ni- 

 trofurazone, and other 5-nitrofurans are toxic to 

 L cells in culture under aerobic conditions but 

 that toxicity and DNA damage increase as oxy- 

 gen content in the culture decreases, Russo et 

 al. (1982) reported liver DNA damage in rats 

 (male, Sprague Dawley, 100-200 g) 72-96 hours 

 after administration of a single oral dose of 56 or 

 1 12 mg/kg of nitrofurantoin <gavage, 0.9% saline 

 with 1% carboxymethylcellulose). Nitrofura- 

 zone, a related 5 nitrofuran, has been shown to 

 bind to nucleic acids and proteins in vivo and in 

 vitro (Tatsumietal., 1977). 



Under aerobic and anaerobic conditions in vitro, 

 nitrofurantoin depletes human erythrocyte glu- 

 tathione, according to Dershwitz and Novak 

 (1982). Minimal binding of nitrofurantoin or 

 metabolites occurs to erythrocyte macromole- 

 cules. Nitrofurantoin was reported to increase 



the rate of superoxide anion radical formation 

 under aerobic conditions from oxyhemoglobin. 

 Under reduced oxygen tension, nitrofurantoin is 

 reduced and requires both an NADPH-depend- 

 cnt fiavoprotein and hemoglobin for superoxide 

 anion radical formation to induce erythrocyte 

 toxicity. 



Peterson et al. (1982b) reported that a potential 

 mechanism of detoxication of nitrofurantoin (or 

 its reaction products) is by a selenium-depen- 

 dent glutathione peroxidase In selenium-defi- 

 cient chicks, the LD50 value is 53 mg/kg, where- 

 as in normal chicks, the LD50 value is 148 

 mg/kg; toxicity can be counteracted by adding 

 selenium, but not vitamin E, back into the diet. 

 Nitrofurantoin in the diet initially decreased 

 glutathione peroxidase activity but not liver glu- 

 tathione, catalase, or superoxide dismutase con- 

 tent, except at highly toxic doses over time. In 

 selenium deficient rats (male, Holtzman) but 

 not in controls, nitrofurantoin (100 mg/kg in 

 feed, 2-5 months after they were weaned) caused 

 renal tubular necrosis and an associated in- 

 crease in serum glutamic-pyruvic transferase 

 activity (Burk and Lane, 1983). 



Epidemiology and Systemic Toxicity 



Adverse reactions to the administration of nitro- 

 furantoin in the treatment of infections in hu- 

 mans have been reported (Delaney et al., 1977; 

 Penn and Griffin, 1982; D'Arcy, 1985). Adverse 

 effects reported included allergic (dermatologic), 

 gastrointestinal, hematologic, hepatic, pul- 

 monary, and neurologic reactions with varying 

 degrees of incidence, time of treatment to onset, 

 and severity of symptoms. The overall incidence 

 of adverse reactions (all types) to nitrofurantoin 

 administration reported worldwide between 

 1953 and 1984 was 0.0028% (D'Arcy, 1985). Al- 

 lergic reactions, acute lung reactions, peripheral 

 neuropathologic effects, and gastrointestinal (in- 

 cluding liver) reactions (in descending order of 

 occurrence) were the most frequently reported 

 (Penn and Ctriffin, 1982; D'Arcy, 1985). 



Nitrofurantoin-induced acute pulmonary reac- 

 tions are characterized by development of fever, 

 cough, and shortness of breath within hours to 

 days after initiation of therapy in humans, ac- 

 cording to Whitcomb and Domby (1978). Eosino- 

 philia and diffuse alveolar or interstitial 



19 



Nitrofurantoin, NTP TR 341 



