Assessment of contribution of BCRP to intestinal absorption of various drugs using portal-systemic blood concentration difference model in mice.

Prediction of the intestinal absorption of new chemical entities (NCEs) is still difficult, in part because drug efflux transporters, including breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp), restrict their intestinal permeability. We have demonstrated that the absorptive quotient (AQ) obtained from the in vitro Caco-2 permeability study would be a valuable parameter for estimating the impact of BCRP on the intestinal absorption of drugs. In this study, in order to assess the correlation between the in vitro AQ for BCRP and in vivo contribution of BCRP on drug absorption, we evaluated the oral absorption of various compounds by portal-systemic blood concentration (P-S) difference method in wild-type (WT), Bcrp(-/-), and Mdr1a/1b(-/-) mice. In addition, we also calculated a rate of BCRP contribution (Rbcrp ). Ciprofloxacin and nitrofurantoin showed the low Rbcrp value (0.05 and 0.15), and their apparent fractions of intestinal absorption in WT mice were 46.5% and 63.7%, respectively. These results suggest that BCRP hardly affects their intestinal absorption in mice. On the other hand, the apparent fraction of intestinal absorption of topotecan and sulfasalazine was significantly lower in WT mice than in Bcrp(-/-) mice. Moreover, their Rbcrp values were 0.42 and 0.79, respectively, indicating the high contribution of BCRP to their oral absorption. Furthermore, in vivo Rbcrp calculated in this study was almost comparable to in vitro AQ obtained from Caco-2 permeability study. This study provides useful concepts in assessing the contribution of BCRP on intestinal absorption in drug discovery and development process.

Development and validation of a fast and sensitive UHPLC-DAD assay for the quantification of nitrofurantoin in plasma and urine.

Nitrofurantoin is an antimicrobial drug that has been used in the treatment of lower urinary tract infections for more than 50 years. Despite its long use, surprisingly little is known of the pharmacokinetics of nitrofurantoin, whereas this is essential to optimize patient treatment. We developed a novel analytical method for the quantification of nitrofurantoin in plasma and urine using ultra-high performance liquid chromatography and diode array detection to allow pharmacokinetic studies in these two matrices. The sample preparation method consisted of protein precipitation for plasma and liquid-liquid extraction for urine. 100 µL was needed for the sample preparation. Furazolidone was used as internal standard. Gradient chromatographic separation was performed on a HSS-T3 column. UV detection was performed at a wavelength of 369 nm. The analysis time was 5 min. The method was successfully validated according to the FDA-guidelines (2018). Linearity was confirmed over a concentration range from 50 to 1250 µg/L in plasma and from 4 to 200 mg/L in urine (r2 > 0.95). Validation results of five QC concentrations for plasma and urine, respectively, are for within-day accuracy <± 13% in both matrices, for between-day accuracy <± 7% and <± 9%, for within-day precision <10% and <4% and for between-day precision <10% and <5%. Plasma samples are stable for seven days at 4 °C, and for 2 years at -20 °C and-80 °C. Urine samples are stable for at least seven days at 4 °C and at room temperature and for 2 years at -20 °C andat -80 °C, except from the lower concentrated samples, which are only stable at -80 °C. All samples were kept from daylight using amber colored glassware. The presented method meets all validation requirements and was successfully used in a clinical study where the pharmacokinetics of nitrofurantoin were investigated in healthy volunteers. The easy sample preparation method and the short analysis time make this method suitable for use during routine clinical practice to study the pharmacokinetics of nitrofurantoin.

Quantitation of nitrofurantoin in human plasma by liquid chromatography tandem mass spectrometry.

A reliable, selective and sensitive LC-MS/MS assay has been proposed for the determination of nitrofurantoin in human plasma. The analyte and nitrofurazone were extracted from 100 µL of human plasma via SPE on Strata-X 33 µm extraction cartridges. Chromatography was done on a BDS Hypersil C18 (100 mm × 4.6 mm, 5 µm) column under isocratic conditions. Quantitation was done using the multiple reaction monitoring (MRM) mode for deprotonated precursor to product ion transitions of nitrofurantoin (m/z 237.0 → 151.8) and nitrofurazone (m/z 197.0 → 123.9). The limit of detection and the lowest limit of quantitation of the method were 0.25 ng mL-1 and 5.00 ng mL-1, respectively, with a linear dynamic range of 5.00-1500 ng mL-1 for nitrofurantoin. The intra- -batch and inter-batch precision (RSD, %) was ≤ 5.8 %, while the mean extraction recovery was > 92 %. The method was successfully applied to a bioequivalence study of a 100 mg nitrofurantoin capsule formulation in 36 healthy subjects.

In vivo inhibition of BCRP/ABCG2 mediated transport of nitrofurantoin by the isoflavones genistein and daidzein: a comparative study in Bcrp1 (-/-) mice.

PURPOSE: The aim of this study was to determine in vivo inhibition by the isoflavones genistein and daidzein of nitrofurantoin (NTF), a well-known substrate of the ABC transporter BCRP/ABCG2. METHODS: MDCKII cells and their human BCRP- and murine Bcrp1-transduced subclones were used to establish inhibition in transepithelial transport assays. Bcrp1(-/-) and wild-type mice were coadministered with nitrofurantoin (20 mg/kg) and a mixture of genistein (100 mg/kg) and daidzein (100 mg/kg). RESULTS: Transepithelial NFT transport was inhibited by the isoflavones. Plasma concentration of NTF at 30 min was 1.7-fold higher (p ≤ 0.05) in wild-type mice after isoflavone administration. AUC values were not significantly different. BCRP/ABCG2-mediated secretion into milk was inhibited since milk/plasma ratios were lower in wild-type mice with isoflavones (7.1 ± 4.2 vs 4.2 ± 1.6, p ≤ 0.05). NTF bile levels were significantly decreased by isoflavone administration in wild-type animals (8.8 ± 3.4 µg/ml with isoflavones vs 3.7 ± 3.3 µg/ml without isoflavones). CONCLUSION: Our data showed that in vivo interaction of high doses of soy isoflavones with BCRP substrates may affect plasma levels but the main effect occurs in specific target organs, in our case, liver and mammary glands.

Milk secretion of nitrofurantoin, as a specific BCRP/ABCG2 substrate, in assaf sheep: modulation by isoflavones.

Studies on residues in milk used for human consumption have increased due to health concerns and priority interest in the control of potentially risky drugs. The protein BCRP/ABCG2, present in the mammary epithelia, actively extrudes drugs into milk and can be modulated by isoflavones. Nitrofurantoin is a specific BCRP substrate which is actively excreted into milk by this transporter. In this research, we studied nitrofurantoin transport into milk in four experimental groups: G1-calves fed forage with isoflavones; G2-calves fed forage with isoflavones and administered exogenous genistein and daidzein; G3-calves fed forage without isoflavones; G4-calves fed forage without isoflavones and administered exogenous genistein and daidzein. Results show increased levels of nitrofurantoin in milk from calves without isoflavones (G3) and decreased nitrofurantoin residues in milk when isoflavones were present, either by forage (G1 and G2) or by exogenous administration (G4). The values of C(max) in milk were significantly lower in those groups with isoflavones in forage (G1, G2). Plasma levels were low and unmodified among the groups. Inter-individual variation was high. All these results seem to point to a feasible control of drug secretion into milk through isoflavones in the diet when the drug is a good BCRP/ABCG2 substrate.

Effect of pregnancy on nitrofurantoin disposition in mice.

We investigated the effect of pregnancy on nitrofurantoin (NFT) disposition in wild-type and Bcrp1(-/-) mice. Pregnant and non-pregnant mice were administered NFT intravenously (5 mg/kg) or orally (10 mg/kg). Blood samples were collected at various times (5-60 min) after drug administration, plasma NFT concentrations determined by HPLC/UV, and pharmacokinetic parameters estimated. Dose-normalized area under the plasma concentration-time curve (AUC), terminal plasma half-life (T(1/2)), total plasma clearance (CL), and steady-state volume of distribution (V(ss)) of intravenous NFT in wild-type or Bcrp1(-/-) mice were not altered by pregnancy. After oral administration, pregnancy did not affect dose-normalized AUC of NFT in wild-type mice; however, dose-normalized AUC in Bcrp1(-/-) mice was decreased by approximately 70% by pregnancy. In conclusion, since Bcrp1 plays a minor role in the systemic clearance of NFT in female mice, pregnancy did not affect disposition of intravenous NFT despite the fact that Bcrp1 expression in the liver and kidney of mice is significantly induced by pregnancy. On the other hand, pregnancy may affect expression and activity of certain intestinal efflux transporters and/or metabolic enzymes in Bcrp1(-/-) mice, resulting in a drastic decrease in the systemic exposure of oral NFT in pregnant Bcrp1(-/-) mice.

Breast cancer resistance protein 1 limits fetal distribution of nitrofurantoin in the pregnant mouse.

The efflux transporter, the breast cancer resistance protein (BCRP), is most abundantly expressed in the apical membrane of the placental syncytiotrophoblasts, indicating that it could play an important role in protecting the fetus by limiting xenobiotic/drug penetration across the placental barrier. In the present study, we examined whether Bcrp1, the murine homolog of human BCRP, limits fetal distribution of the model BCRP/Bcrp1 substrate, nitrofurantoin (NFT), in the pregnant mouse. NFT was administered i.v. to FVB wild-type and Bcrp1(-/-) pregnant mice. The maternal plasma samples and fetuses were collected at various times (5-60 min) after drug administration. The NFT concentrations in the maternal plasma samples and homogenates of fetal tissues were determined by a high-performance liquid chromatography/UV assay. Although the maternal plasma area under the concentration-time curve (AUC) of NFT in the Bcrp1(-/-) pregnant mice (97.4 +/- 10.0 microg . min/ml plasma) was only slightly (but significantly) higher than that in the wild-type pregnant mice (78.4 +/- 6.0 microg . min/ml plasma), the fetal AUC of NFT in the Bcrp1(-/-) pregnant mice (1493.0 +/- 235.3 ng . min/g of fetus) was approximately 5 times greater than that in the wild-type pregnant mice (298.6 +/- 77.4 ng . min/g of fetus). These results clearly suggest that Bcrp1 significantly limits fetal distribution of NFT in the pregnant mouse, but has only a minor effect on the systemic clearance of the drug.

The breast cancer resistance protein (BCRP/ABCG2) affects pharmacokinetics, hepatobiliary excretion, and milk secretion of the antibiotic nitrofurantoin.

Nitrofurantoin is a commonly used urinary tract antibiotic prescribed to lactating woman. It is actively transported into human and rat milk by an unknown mechanism. Our group has demonstrated an important role of the breast cancer resistance protein (BCRP/ABCG2) in the secretion of xenotoxins into the milk. This ATP-binding cassette drug efflux transporter extrudes xenotoxins from cells in intestine, liver, mammary gland, and other organs, affecting the pharmacological and toxicological behavior of many compounds. We investigated whether Bcrp1 is involved in the pharmacokinetic profile of nitrofurantoin and its active secretion into the milk. Using polarized cell lines, we found that nitrofurantoin is efficiently transported by murine Bcrp1 and human BCRP. After oral administration of 10 mg/kg nitrofurantoin, the area under the plasma concentrationtime curve in Bcrp1 knockout mice was almost 4-fold higher than in wild-type mice (148.8 +/- 30.4 versus 37.5 +/- 6.8 min x microg/ml); and after i.v. administration (5 mg/kg), 2-fold higher (139.2 +/- 22.0 versus 73.9 +/- 9.0 min x microg/ml). Hepatobiliary excretion of nitrofurantoin was almost abolished in Bcrp1 knockout mice (9.6 +/- 3.2 versus 0.2 +/- 0.1% in wild-type and Bcrp1 knockout mice, respectively). The milk-to-plasma ratio of nitrofurantoin was almost 80 times higher in wild-type compared with Bcrp1 knockout lactating female mice (45.7 +/- 16.2 versus 0.6 +/- 0.1). Nitrofurantoin elimination via milk was quantitatively even higher than hepatobiliary elimination. We conclude that Bcrp1 is an important determinant for the bioavailability of nitrofurantoin and the main mechanism involved in its hepatobiliary excretion and secretion into the milk.

Determination of nitrofurantoin drug in pharmaceutical formulation and biological fluids by square-wave cathodic adsorptive stripping voltammetry.

Nitrofurnation is an antibacterial drug. It is used in the treatment of initial or recurrent urinary tract infections caused by susceptible organisms. The cyclic voltammogram of the drug in Britton-Robinson buffers (pH 2-11) exhibited a single well-defined cathodic peak at the hanging mercury drop electrode, that due to the reduction of its nitro group to the amine stage. A fully validated, sensitive, and reproducible developed procedure was described for determination of the drug in bulk form, pharmaceutical formulation, human serum and human urine using, square-wave cathodic adsorptive stripping voltammetry. The optimal experimental parameters for the drug assay were: accumulation potential = -0.4 V (vs. Ag/AgCl/ KCl(s)), accumulation time = 40 s, frequency = 120 Hz, pulse amplitude = 50 mV and scan increment = 10 mV in Britton-Robinson buffer (pH 10). A mean percentage recovery of 100.68 +/- 0.17 (n = 5) and a detection limit of 1.32 x 10(-10) M of bulk drug were achieved. Applicability to assay of the drug in pharmaceutical formulation, human serum and human urine was studied and illustrated. The mean percentage recoveries were found as: 101.49 +/- 0.65, 103.94 +/- 0.73 and 101.98 +/- 0.52 (n = 5) in pharmaceutical formulation, human serum and human urine, respectively. Detection limits of 2.86 x 10(-10) M and 5.77 x 10(-10) M nitrofurantoin were achieved in human serum and urine, respectively.

Active transport of nitrofurantoin into human milk.

STUDY OBJECTIVE: To determine the extent to which nitrofurantoin is transferred into human milk. DESIGN: Prospective, single-dose pharmacokinetic study. SETTING: University-affiliated clinical research center. PATIENTS: Four healthy lactating women 8-26 weeks postpartum. INTERVENTION: All subjects received a single, oral, 100-mg dose of nitrofurantoin macrocrystals with food. Serial serum and milk samples were obtained and analyzed by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Milk pH, milk fat partitioning, and protein binding in serum and milk were determined. Predicted milk:serum ratio (M:S) was compared with the observed M:S. Nitrofurantoin M:S predicted was 0.28+/-0.05, whereas M:S observed was 6.21+/-2.71. Average milk concentration was 1.3 mg/L, and estimated suckling infant dosage was 0.2 mg/kg/day or 6% of maternal dose (mg/kg). CONCLUSIONS: Nitrofurantoin is actively transported into human milk, achieving concentrations in milk greatly exceeding those in serum. Concern is warranted for suckling infants younger than 1 month old, or for infants with a high frequency of glucose-6-phosphate dehydrogenase deficiency or sensitivity to nitrofurantoin.

Active transport of nitrofurantoin into rat milk.

Most xenobiotics are transferred into milk by passive diffusion; however, some drugs have been reported to accumulate in milk as a result of active transport. In the present study, lactating Sprague Dawley rats were used to characterize the transfer of nitrofurantoin into milk. The observed milk to serum concentration ratio (M/S) of 31.1+/-4.0 was 100 times higher than the M/S predicted by diffusion (0.3+/-0.1), indicative of an active transfer into milk. Randomized crossover infusions of nitrofurantoin (0.5mg/h) in the absence and presence of a cimetidine infusion regimen (15mg/h) resulted in the corresponding mean M/S of 29.5+/-5.4 vs. 30.7+/-5.0 and systemic clearance (Cls) of 2.7+/-0.7 vs. 2.2+/-0.4 L/h/kg, respectively. Nitrofurantoin infusions (0.5mg/h) in the absence and presence of a higher cimetidine infusion regimen (30mg/h) resulted in the corresponding mean values for M/S of 23.0+/-7.7 vs. 19.8+/-5.9 and Cls of 2.8+/-0.4 vs. 1.4+/-0.4L/h/kg, respectively. Only the decrease in Cls at the higher cimetidine infusion was statistically significant. These observations provide evidence that nitrofurantoin is actively transported into rat milk by a transporter that is not inhibited by cimetidine. These data suggest the presence of at least two distinct mammary epithelial transporter systems, one that transports organic cations (e.g., cimetidine) and another for anions (e.g., nitrofurantoin).

Active transport of nitrofurantoin across the mammary epithelium in vivo.

Nitrofurantoin is a commonly used urinary tract antibiotic that has been found at high concentrations in human milk. In vivo studies in rats were carried out to determine the mechanism by which this drug crosses the mammary epithelium. Lactating rats were gavage-fed with nitrofurantoin, and their milk and plasma levels of the antibiotic were measured at intervals up to 8 hr. The average milk-to-plasma (M/P) ratio, calculated from the areas under the milk and plasma curves, respectively, was 23 compared with a ratio predicted to be about 0.3 on the basis of lipid partitioning and protein binding determinations. M/P ratios for two nitrofurantoin congeners were also calculated. The neutral compound furazolidone had a M/P ratio of about 1, as predicted, whereas the basic compound furaltadone had a M/P ratio of 3.49 compared with a predicted ratio of 1.4. These data suggest that nitrofurantoin and, to a lesser extent, furaltadone are actively transported across the mammary epithelium into milk.

Sensitive determination of nitrofurantoin in human plasma and urine by high-performance liquid chromatography.

A highly sensitive and selective HPLC method was developed and validated for the determination of nitrofurantoin in human plasma and urine. The method involves the liquid-liquid extraction of drug and internal standard from plasma with ethyl acetate followed by evaporation and reconstitution in mobile phase. Urine samples were simply diluted with purified water. UV detection was done at 370 nm. The limit of quantification for nitrofurantoin in plasma was 0.010 micrograms/ml. In urine nitrofurantoin could be quantified down to 0.380 microgram/ml. Linearity was proven over the whole calibration range in plasma (2.48-0.0100 microgram/ml) as well as in urine (187 micrograms/ml-0.380 microgram/ml). The method was validated according to Good Laboratory Practice guidelines and its suitability was demonstrated by analysis of samples from a pharmacokinetic study.

Comparative human bioavailability study of macrocrystalline nitrofurantoin and two prolonged-action hydroxymethylnitrofurantoin preparations.

This single-blind crossover study compared the human bioavailability of macrocrystalline nitrofurantoin (Furadantine MC) and two prolonged-action hydroxymethylnitrofurantoin formulations (Urfadyn PL, bid, and Uridurine, tid), based on plasma nitrofurantoin concentrations and urinary nitrofurantoin excretion. The drugs were administered to 16 healthy females for a single day according to the recommended daily dosages. For comparison, Furadantine MC was administered both at the qid dosage recommended by the manufacturer and at tid dosage. Pharmacokinetic parameters determined were maximum plasma concentration after first dose, minimum plasma concentration after first dose, area under the plasma concentration-time curve (AUC), cumulative renal excretion over 30 hours (ARE), overall renal clearance, total body clearance, and bioavailability relative to Furadantine MC qid, based on plasma AUC (F) and ARE (Fren). F for Furadantine MC 100 mg tid was 108 +/- 25 percent (mean +/- SD); for Uridurine 100 mg tid and Urfadyn PL 100 mg bid, F equalled 86 +/- 33 percent and 53 +/- 20 percent (p less than 0.05), respectively. A similar relationship was observed between Fren for Furadantine MC 100 mg qid and the respective Fren of Furadantine MC 100 mg tid, Uridurine 100 mg tid, and Urfadyn PL 100 mg bid. No significant difference was found between the respective F and Fren of each of the drugs studied. Although bioavailability was comparable for Furadantine MC tid and qid, the single-day design of these studies precludes inferring that these dosage schedules are therapeutically equivalent. However, the significantly lower relative bioavailabilities for the prolonged-action hydroxymethylnitrofurantoin formulations suggest that Urfadyn PL 100 mg bid and Uridurine 100 mg tid are not pharmacokinetically equivalent to Furadantine MC.

Formation of methemoglobin by photoactivation of nitrofurantoin or of 5-nitrofurfural in rats exposed to UV-A light.

The antibacterial drug nitrofurantoin (NFT) is notorious for causing hemolytic anemia, which may be related to the methemoglobinemia, another side-effect of NFT. As NFT is photolabile, and nitrite, well known as a MetHb generator, is an important photoproduct of NFT, it seems not unlikely that light is a cause of NFT-induced MetHb formation. When rats were irradiated with UV-A immediately after oral NFT administration, the amount of MetHb significantly increased: 0.97 +/- 0.37% n = 36 (P less than 0.001 Student's t-test, control value: 0.5%). An increase in MetHb was also observed with rats simultaneously exposed to UV-A and the major photodecomposition product of NFT, viz. 5-nitrofurfural. In addition in vitro experiments proved the formation of MetHb as a result of photoactivation of NFT. Nitrite, photochemically formed from nitrofurfural and from the metabolite nitrofuroic acid, plays an important role. A dark reaction of the other photoproduct, nitrofurfural, with hemoglobin also appeared to cause a considerable amount of MetHb in vitro. However, because of rapid deactivation of nitrofurfural by either photodecomposition or metabolism, this dark reaction is not expected to contribute to the in vivo MetHb formation.

Evaluation of genotoxic activity in the blood and urine of guinea pigs treated with nifurtimox and benznidazole.

1. The mutagenicity of serum and urine from guinea pigs treated with a single oral dose (500 mg/kg) of benznidazole and nifurtimox was assayed using the Salmonella/plate incorporation test with strain TA 100 and a nitroreductase-deficient derivative, TA 100NR. 2. The urine and blood of animals treated with nifurtimox were not mutagenic for either tester strain. 3. The urine and blood of animals receiving benznidazole were mutagenic to the TA 100 but not to the TA 100NR strain. Similar results were obtained with nitrofurantoin-treated animals. Maximum mutagenicity values were obtained in serum and urine of treated animals 90 min and 24 h after administration, respectively. 4. Mutagenicity induced by benznidazole in the serum and urine of treated animals was not altered when assayed in anaerobic environments. 5. These results indicate that benznidazole and nifurtimox are not metabolized by the mammalian host into stable mutagenic derivatives detectable by the Ames test. Based on these data, we suggest that the potential cancer risk to patients treated with these drugs is small but should be further evaluated.

Dose- and time-dependent kinetics of the renal excretion of nitrofurantoin in the rabbit.

A pharmacokinetic study on the renal excretion of nitrofurantoin was carried out in rabbits at doses ranging from 0.5 to 15 mg/kg. With increasing dose, nonlinear kinetics were observed in the tubular secretion, which appeared to show dose and time dependence. The disposition of nitrofurantoin after intravenous injection is well described by a one-compartment model with simultaneous first-order nonrenal elimination and renal elimination, which consists of glomerular filtration, active tubular secretion conforming to the Michaelis-Menten equation, and reabsorption clearance by nonionic diffusion. Plasma and urinary excretion data after intravenous injection of nitrofurantoin were fitted to this model. When the Michaelis constant was loosely restricted at a constant value, the maximum velocity decreased with increasing dose of nitrofurantoin. However, the Michaelis constant apparently increased with increasing dose when the maximum velocity was loosely restricted at a constant value. Although the results of this fitting suggested that the former case may occur in the active tubular secretory system, the latter case could not be completely eliminated because of limited data. The implications of these results are discussed on the basis of the available published data.

[Pharmacokinetics of nitrofurantoin in the bodies of pregnant rats]. / Farmakokinetyka nitrofurantoiny (NTF) w ustroju szczurów ciezarnych.

The investigation of nitrofurantoin (NTF) pharmacokinetics in pregnant rats was undertaken to estimate its cumulation in the fetus unit. It was found that pharmacokinetics of NTF is dose-dependent in non-pregnant rats. The biological half-life time increased from 0.24 to 0.41 and 0.72 h for NTF doses 10.20 and 40 mg/kg, respectively. The elimination of NTF was diminished in pregnant rats. The pharmacokinetic analysis revealed a possibility of strong NTF accumulation in the pregnant rats (increased K12/K21 ratio). Taking into account increased renal function in pregnancy, one may suspect that decreased elimination of NTF was rather caused by its significant cumulation in the changed tissue compartment.

Studies on the mechanism of nitrofurantoin-mediated red cell toxicity.

The mechanism of nitrofurantoin-mediated depletion of red cell reduced glutathione (GSH) was investigated. Nitrofurantoin caused cellular depletion of GSH in vitro under aerobic and oxygen-depleted conditions, an effect which could be partially inhibited by coincubation with the hemeprotein ligand ethyl isocyanide, or completely prevented by coincubation with 2'-AMP, an inhibitor of NADPH-dependent reductase enzymes. Covalent binding of nitrofurantoin to red cell macromolecules appeared to be a minor process and was not substantially inhibited by either ethyl isocyanide or 2'-AMP. Covalent binding was only slightly greater under oxygen-depleted conditions. Nitrofurantoin increased the rate of superoxide formation in red cell lysate, an effect inhibited by ethyl isocyanide but not by 2'-AMP. These data suggest different mechanisms for nitrofurantoin-mediated depletion of GSH under aerobic and oxygen-depleted conditions. In the presence of oxygen, nitrofurantoin causes the release of superoxide from oxyhemoglobin. The superoxide thus formed may deplete GSH via several mechanisms. In the absence of oxygen, nitrofurantoin is reduced to reactive metabolites via reactions which appear to require the participation of both an NADPH-dependent flavoprotein and hemoglobin.

Experimental and clinical pharmacokinetics of nitrofurantoin in the early period of life.

The investigation of pharmacokinetics showed age-dependent rate of nitrofurantoin elimination in rats. Nitrofurantoin half-life of 0.41 hr in adults was prolonged to 0.95 hr in 2-weeks-old rats. Nitrofurantoin excretion rate was decreased in children younger than 2 years. Older children excreted in urine 44.32 +/- 16.07 and younger 25.07 +/- 5.7 per cent of the given dose of nitrofurantoin, indicating the lower capacity for nitrofurantoin elimination via kidneys.