I. INTRODUCTION 



Nitrofurantoin is excreted rapidly in adult rats 

 (male and female, Wistar, at least 33 days old), 

 but not in young rats (male and female, Wistar, 

 5-15 days old) due to greater renal tubular reab- 

 sorption rates in young rats (Braunlich et al., 

 1978). Wierzba et al. (1982) reported that nitro- 

 furantoin excretion is age dependent in both hu- 

 mans and rats. Patients under 2 years of age 

 (sex unspecified) with a urinary tract infection 

 and normal renal function excreted 25% ± 5.7% 

 of their first dose (oral) after 12 hours at an ini- 

 tial excretion rate of 0.68 ± 0.23 mg/hour Pa- 

 tients older than 2 years of age (sex and age 

 range not given, same clinical conditions) ex- 

 creted 44% ± 16% at an initial rate of 4.55 ± 

 2.64 mg/hour. In comparison, Wierzba et al. re- 

 ported that intravenous administration of nitro- 

 furantoin (20 mg/kg) to 2-week-old or 2- to 

 3-month old rats (Wistar, sex unspecified) re 

 suited in half-life values of 0.95 and 0.41 hours, 

 respectively. 



After a single oral dose of nitrofurantoin (ga- 

 vage, 25 mg/kg) to female albino rats (strain, 

 age, and sex unspecified), 52% and 2.6% nitrofu- 

 rantoin (percentage total dose) were recovered in 

 the urine and feces, respectively (Paul, M.F , et 

 al., 1960). When administered intravenously to 

 rats (strain, age and sex unspecified) to specific 

 organ sites of the digestive tract (25 or 100 

 mg/kg), nitrofurantoin was absorbed rapidly via 

 the small intestine, metabolized by liver, intes- 

 tine, and kidney, and excreted (half-life of 25 

 minutes) in the urine (50% recovered as nitrofu- 

 rantoin) (Buzard et al., 1961). Veronese et al. 

 (1974) reported that after intravenous adminis- 

 tration of nitrofurantoin to rats (male, Sprague 

 Dawley, 150-200 g), 16%-30% of the total dose 

 was recovered in the urine The proportion of ni- 

 trofurantoin or metabolite recovered was in- 

 versely related to dose; relative urinary excre- 

 tion of nitrofurantoin decreased with increasing 

 dose. Statham et al. (1985) compared the phar 

 macokinetics between control and vitamin 

 R-deficient male Sprague Dawley rats (age un- 

 specified, 200 g) administered nitrofurantoin 

 subcutaneously (15 mg/kg) and found that ni- 

 trofurantoin was rapidly absorbed and cleared 

 from blood, lung, liver, and kidney in a biphasic 

 manner. Metabolism of nitrofurantoin occurred 

 in control animals, but there were increased 

 levels of unchanged nitrofurantoin in vitamin 



E-deficient rats. Urinary excretion was 68% of 

 the total dose administered in control rats and 

 35% in vitamin R-deficient rats. 



Intravenous administration of nitrofurantoin 

 (1.5-24 mg/kg) to adult male beagles (10-16 kg) 

 stimulated bile secretion, and nitrofurantoin 

 was excreted in bile (at 6 mg/kg, 22.6% ± 4.7% 

 total dose) and urine (24.1% ± 4.7%) (Conklin 

 and Wagner, 1971). In these studies, carbon 

 tetrachloride administration was found to im 

 pair bile How and nitrofurantoin excretion Ni- 

 trofurantoin (after intravenous administration) 

 is excreted in bile, reabsorbed, and enterohepat- 

 ically recirculated (Conklin et al , 1973). 



Oral administration of nitrofurantoin also may 

 result in the excretion of nitrofurantoin in the 

 milk of lactating humans ( Varsano et al., 1973), 

 rats, and dogs (Paul, M.F , et al , 1960). Admin- 

 istration of nitrofurantoin (oral, 100 or 200 mg) 

 to lactating women with normal glucose-6-phos- 

 phate dehydrogenase levels who had stopped 

 nursing resulted in excretion of nitrofurantoin 

 in their milk. The milk to serum ratio was ap- 

 proximately 29 in those with detectable levels. 

 Sixteen hours after being dosed, rats (age, sex, 

 and strain unspecified, 100 mg/kg) excreted 5 

 mg/liter, and dogs (age, sex, and strain unspeci- 

 fied, 20 mg/kg) excreted 2.33 mg/liter. 



Acute Toxicity 



Acute toxicity varies somewhat between rats 

 (LD5o = 112 mg/kg by intraperitoneal injection; 

 604 mg/kg by gavage; vehicle, 5%-15% acacia in 

 water; male, Sprague Dawley, 180 g; Preti, 

 1970) and mice (LD5o=150 mg/kg by intraperi- 

 toneal injection; 360 mg/kg by gavage; vehicle, 

 age, and sex unspecified; NIOSH, 1983). The 

 oral TD[^„ for humans is 80 mg/kg. Dietary de- 

 ficiencies in both selenium (Burk and Lane, 

 1983) and vitamin E (Boyd et al , 1979b) in- 

 creased the acute toxicity of nitrofurantoin to 

 rats (male, Holtzman and Sprague Dawley, 

 respectively). 



Cellular and Subcellular Toxicity 



In vitro studies indicate that under aerobic con- 

 ditions, reduction of nitrofurantoin stimulates 

 consumption of oxygen and production of super- 

 oxide anion free radical and hydrogen peroxide 



Nitrofurantoin, NTP TR 341 



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