Nitrofurantoin disposition

Hoener, Betty‐Ann; Patterson, Sean E.

doi:10.1038/clpt.1981.115

Cited by 42 publications

(12 citation statements)

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“…While the bioavailability of NFT in humans was approximately 90%,31 the bioavailability of NFT in rodents and rabbits was relatively low (e.g., 30% in rabbits) 32, 33. In the present study, we showed that the oral bioavailability of NFT in wild‐type female mice was 40–55% (Tab.…”

Section: Discussionsupporting

confidence: 46%

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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: 46%

“…The unbound fraction of NFT in pregnant wild‐type mice (43.6 ± 3.7%) was slightly but significantly lower than that in non‐pregnant wild‐type mice (64.4 ± 6.3%). Unbound fraction of NFT in human plasma was approximately 40% 31…”

Section: Resultsmentioning

confidence: 96%

Effect of Pregnancy on Nitrofurantoin Disposition in Mice

Zhang

Zhou

Unadkat

et al. 2009

Journal of Pharmaceutical Sciences

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“…Similar to rats, nitrofurantoin is well absorbed in humans (Hoener and Patterson, 1981); oral exposure and urinary excretion of nitrofurantoin is unaffected in the subjects with the ABCG2 421 AA genotype (Adkison et al, 2008). On the other hand, Abcg2 had a more pronounced effect on oral exposure of sulfasalazine in rats relative to humans.…”

Section: Discussionmentioning

confidence: 78%

Deletion ofAbcg2Has Differential Effects on Excretion and Pharmacokinetics of Probe Substrates in Rats

Huang

Tchaparian

et al. 2012

J Pharmacol Exp Ther

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This study was designed to characterize breast cancer resistance protein (Bcrp) knockout Abcg2(Ϫ/Ϫ) rats and assess the effect of ATP-binding cassette subfamily G member 2 (Abcg2) deletion on the excretion and pharmacokinetic properties of probe substrates. Deletion of the target gene in the Abcg2(Ϫ/Ϫ) rats was confirmed, whereas gene expression was unaffected for most of the other transporters and metabolizing enzymes. Biliary excretion of nitrofurantoin, sulfasalazine, and compound A [2-(5-methoxy-2-((2-methyl-1,3-benzothiazol-6-yl)amino)-4-pyridinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one] accounted for 1.5, 48, and 48% of the dose in the Abcg2(ϩ/ϩ) rats, respectively, whereas it was decreased by 70 to 90% in the Abcg2(Ϫ/Ϫ) rats. Urinary excretion of nitrofurantoin, a significant elimination pathway, was unaffected in the Abcg2(Ϫ/Ϫ) rats, whereas renal clearance of sulfasalazine, a minor elimination pathway, was reduced by Ͼ90%. Urinary excretion of compound A was minimal. Systemic clearance in the Abcg2(Ϫ/Ϫ) rats decreased 22, 43 (p Ͻ 0.05), and 57%, respectively, for nitrofurantoin, sulfasalazine, and compound A administered at 1 mg/kg and 27% for compound A administered at 5 mg/kg. Oral absorption of nitrofurantoin, a compound with high aqueous solubility and good permeability, was not limited by Bcrp. In contrast, the absence of Bcrp led to a 33-and 11-fold increase in oral exposure of sulfasalazine and compound A, respectively. These data show that Bcrp plays a crucial role in biliary excretion of these probe substrates and has differential effects on systemic clearance and oral absorption in rats depending on clearance mechanisms and compound properties. The Abcg2(Ϫ/Ϫ) rat is a useful model for understanding the role of Bcrp in elimination and oral absorption.

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“…Toxic nitrofurantoin metabolites have previously been implicated in neurologic, hepatic, and pulmonary adverse effects. 14, 15 Drug interactions due to the cytochrome P450 and/or Pglycoprotein systems are not likely the cause of our patient's hepatic and pulmonary changes. Nitrofurantoin is not known to be affected by either system, and in vitro data indicate extremely low P-glycoprotein inhibition by flu- conazole.…”

Section: Discussionmentioning

confidence: 94%