I. INTRODUCTION 



(Conklin and Wagner, 1971). Sites of optimal 

 absorption of nitrofurantoin in the gastrointes- 

 tinal tract may vary between humans (duo- 

 denum) (Conklin and Hailey, 1969) and rodents 

 (mice, ileum) (Maiti and Banerjee, 1978). 



After a single oral administration of 50 or 150 

 mg nitrofurantoin to healthy male volunteers 

 (19-43 years old, 63-96 kg), the terminal elimi- 

 nation half-life was 1 .2 or 1.7 hours, respectively 

 (Liedtke et al., 1980). Intravenous administra- 

 tion of 50 mg nitrofurantoin (male, 25-35 years 

 old, 62-80 kg) resulted in a half-life value of 58 

 ± 15 minutes, and 47% ± 13% and 12% ± 3% 

 were excreted unchanged as parent compound 

 and aminofurantoin, respectively, in the urine 

 (Floener and Patterson, 1981). These half-life 

 values are significantly longer than those in 

 earlier reports that suggested approximately 

 50% of the administered dose was excreted in 

 humans within 20-30 minutes (Reckendorf et 

 al., 1962; Paul and Paul, 1964; Schirmeister et 

 al, 1965; Sachs et al., 1968; Conklin, 1972a; 

 Bron et al , 1979). Liedtke et al. (1980) sug- 

 gested that this discrepancy in half-life is due to 

 improved analytical methods (high-performance 

 liquid chromatography vs. spectrophotometry). 

 A decrease in urine pH increased the half-life, 

 which suggests that changes in pH may influ- 

 ence dissolution, bioavailability, and/or the rate 

 of excretion in humans (Bron et al., 1979). Ab- 

 sorption of nitrofurantoin is increased with the 

 presence of food in the gastrointestinal tract 

 (Bates et a!., 1974; Rosenberg and Bates, 1976; 

 Hoener and Patterson, 1981). Absorption of ni- 

 trofurantoin in humans (male, 21-32 years old) 

 was also influenced by the presence and size of 

 the macrocrystals in the formulation (Bates et 

 al., 1974; Meyer et al., 1974). During conditions 

 of renal impairment, nitrofurantoin excretion is 

 greatly diminished (Kunin, 1972). 



Under aerobic conditions, the reduction of nitro- 

 furantoin by the addition of an electron to the 5- 

 nitrofuran ring via a nitroreductase, NADPH, 

 and a flavoprotein has been reported to occur in 

 vitro in hepatic and/or lung microsomes from 

 rats (male, CD, 160-180 g. Mason and Holtzman, 

 1975a; male, HLA-SD, 150 g, Boyd et al., 1979a; 

 male, Sprague Dawley, 135-140 g, Sasame and 

 Boyd, 1979), chickens (Leghorn, 8 days old. 



Peterson et al., 1982a), guinea pigs (age and sex 

 not specified, 400-600 g, Leskovac and Popovic, 

 1980), or Erhlich ascites tumor cells (Biaglow et 

 al., 1977). This results in a transient nitroaro- 

 matic anion radical that may react with molecu- 

 lar oxygen, producing superoxide anion free 

 radical, and possibly hydrogen peroxide and the 

 regeneration of nitrofurantoin. Oxidative me- 

 tabolism of the nitrofurantoin side chain has 

 also been reported to occur (Pugh et al., 1972). 

 Jonen and Kaufman (1980) reported that in rats 

 (male, Sprague Dawley, 250-300 g, age not spe- 

 cified), 3-methylcholanthrene and P-nitrofia- 

 vone, but not phenobarbital, pretreatment in 

 creased the clearance of napthofurantoin from 

 the isolated perfused liver and increased the 

 formation of a polar metabolite, similar to a hy- 

 droxylated furan derivative ( l-[[(5-ac(-nitro-4,5- 

 dihydro-4-oxo-2-furanyl)-methylene]amino|-2,4- 

 imidazolidinedione) (Olivard et al., 1976) 



Reductive metabolism of nitrofurantoin under 

 anaerobic conditions has been described in both 

 rodents and bacteria. Without oxygen, nitrofu- 

 rantoin is believed to be permanently reduced to 

 nitroso and/or hydroxy lamine forms (Mason and 

 Holtzman, 1975b, Biaglow et al , 1977; Leskovac 

 and Popovic, 1980). Aufrere et al. ( 1978) studied 

 the reductive metabolism of nitrofurantoin un- 

 der anaerobic conditions with young male 

 Sprague Dawley rats (60 g) and reported that 

 the metabolism of nitrofurantoin was greatest in 

 homogenates of cecum and colon contents of 

 germ-free acclimatized and control rats but not 

 germ-free rats and in liver, small intestine 

 walls, and kidney (in decreasing order of activi- 

 ty) in all groups. Nitrofurantoin was reduced 

 under these conditions to two metabolites, l-[((3- 

 cyano-l-oxopropyD-methylenel-amino 1-2,4- imi- 

 dazolidinedione (major) and l-[[(5-amino-2-fu- 

 ranyl)methylene|-amino|-2,4-imidazolidinedi- 

 one (aminofurantoin) (minor). Two other path- 

 ways were reported by Olivard et al. (1962) to oc- 

 cur in the gastrointestinal tract: reduction of ni- 

 trofurantoin to the 5-aminofuran and acetyla- 

 tion to form the 5-acetamidofuran or 5-diacetyl- 

 aminofuran, and acid hydrolysis of the azo- 

 methine bridge to produce 5-nitro-2-furanocar- 

 boxaldehyde, which may be excreted as 5-nitro- 

 2-furoic acid or as a hydrazine derivative, which 

 may be acetylated and excreted. 



17 



Nitrofurantoin, NTP TR 34 1 



