Reductive and oxidative metabolism of nitrofurantoin in rat liver

Hg, Jonen

doi:10.1007/bf00499260

Cited by 13 publications

(2 citation statements)

References 37 publications

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“…2), which is in the same range as previously reported 33. The studies using rat liver by Jonen34 suggested a minor role of hepatic metabolism in the elimination of NFT in rats. Moreover, Watari et al32 showed that the bioavailability of NFT in rabbits following intraduodenal administration and portal vein infusion was nearly unity.…”

Section: Discussionsupporting

confidence: 85%

Effect of Pregnancy on Nitrofurantoin Disposition in Mice

Zhang

Zhou

Unadkat

et al. 2009

Journal of Pharmaceutical Sciences

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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.

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Section: Discussionsupporting

confidence: 85%

Effect of Pregnancy on Nitrofurantoin Disposition in Mice

Zhang

Zhou

Unadkat

et al. 2009

Journal of Pharmaceutical Sciences

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“…However, Mendgen et al did not evaluate the toxicity and metabolism of FMMHs, and information on metabolism and toxicity of FMMHs is only available for specific drugs and their derivatives. Those studies suggest that knowledge on metabolism and toxicities of FMMHs are important as FMMHs could confer toxicity through metabolism. − The antiepileptic drug, phenytoin (Figure ), that contains a hydantoin scaffold, was studied by several research groups to determine the underlining mechanism for the development of skin rashes observed in 5–10% of patients . These studies showed that phenytoin undergoes hydroxylation to form 5-(4-hydroxyphenyl-)-5-phenylhydantoin (HPPH) that could be further oxidized to the reactive catechol, resulting in the formation of a drug–protein adduct .…”

Section: Introductionmentioning

confidence: 99%

Systematic Evaluation of the Metabolism and Toxicity of Thiazolidinone and Imidazolidinone Heterocycles

Tang

Lee

Packiaraj

et al. 2015

Chem. Res. Toxicol.

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The thiazolidine and imidazolidine heterocyclic scaffolds, i.e., the rhodanines, 2,4-thiazolidinediones, 2-thiohydantoins, and hydantoins have been the subject of debate on their suitability as starting points in drug discovery. This attention arose from the wide variety of biological activities exhibited by these scaffolds and their frequent occurrence as hits in screening campaigns. Studies have been conducted to evaluate their value in drug discovery in terms of their biological activity, chemical reactivity, aggregation-based promiscuity, and electronic properties. However, the metabolic profiles and toxicities have not been systematically assessed. In this study, a series of five-membered multiheterocyclic (FMMH) compounds were selected for a systematic evaluation of their metabolic profiles and toxicities on TAMH cells, a metabolically competent rodent liver cell line and HepG2 cells, a model of human hepatocytes. Our studies showed that generally the rhodanines are the most toxic, followed by the thiazolidinediones, thiohydantoins, and hydantoins. However, not all compounds within the family of heterocycles were toxic. In terms of metabolic stability, 5-substituted rhodanines and 5-benzylidene thiohydantoins were found to have short half-lives in the presence of human liver microsomes (t1/2 < 30 min) suggesting that the presence of the endocyclic sulfur and thiocarbonyl group or a combination of C5 benzylidene substituent and thiocarbonyl group in these heterocycles could be recognition motifs for P450 metabolism. However, the stability of these compounds could be improved by installing hydrophilic functional groups. Therefore, the toxicities and metabolic profiles of FMMH derivatives will ultimately depend on the overall chemical entity, and a blanket statement on the effect of the FMMH scaffold on toxicity or metabolic stability cannot and should not be made.

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Disposition of Nitrofurantoin and Nitrofurazone in the Isolated Perfused Rat Kidney

Hoener

Krueger

1984

Journal of Pharmaceutical Sciences

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Reductive and oxidative metabolism of nitrofurantoin in rat liver

Cited by 13 publications

References 37 publications

Effect of Pregnancy on Nitrofurantoin Disposition in Mice

Effect of Pregnancy on Nitrofurantoin Disposition in Mice

Systematic Evaluation of the Metabolism and Toxicity of Thiazolidinone and Imidazolidinone Heterocycles

Disposition of Nitrofurantoin and Nitrofurazone in the Isolated Perfused Rat Kidney

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