Absorption of orally, intraduodenally, and intraileally administered nitrofurantoin in man

Wagner, Daniel; Nesbitt, John D.; Conklin, John; Hailey, Francis J.

doi:10.1016/0378-5173(89)90308-6

Cited by 3 publications

(4 citation statements)

References 5 publications

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“…In the literature, several data sets have been published over the past decades in which NFT was administered to rabbits [ 17 ], rats [ 23 , 28 ], and humans [ 29 ]. We digitized these data from the original publications, so they could be compared to PBPK model predictions.…”

Section: Resultsmentioning

confidence: 99%

“…Animal PK studies have indicated that NFT kinetics are not linearly proportional to the administered dose [ 12 , 17 , 19 ]. At the same time, human PK exhibits high variability [ 2 , 29 , 34 ]. Thus, there is a strong need to understand the relationship between physiological factors, NFT exposure, and its disposition, as this might help us to understand the quantitative contribution of kinetics to the risk of hepatic adverse events.…”

Section: Discussionmentioning

confidence: 99%

“…Rat kinetics data upon IV or oral dosing were taken from [ 23 , 28 ]. We extracted human time course plasma data upon a single oral administration of three different doses (50, 100, and 200 mg) a day from [ 29 ]. Our strategy for model development and validation based on the independent data sets from the three species involved the following steps: First, we calibrated the model using IV dose kinetics data from rabbits.…”

Section: Methodsmentioning

confidence: 99%

“…We also varied age from 25 to 40 using a uniform distribution and scaled the human physiological parameters based on age (see Section 2). Based on the extrapolated model (i.e., without further model calibration) and using oral doses as input, we predicted the kinetics of NFT in human plasma and compared these to published measurements from [29] (Figure 6). The model captured the dose-dependent increase in the plasma concentration well.…”

Section: Extrapolation Of Pbpk Model From Rats and Rabbits To Humansmentioning

confidence: 99%

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Development of a Physiologically Based Pharmacokinetic Model for Nitrofurantoin in Rabbits, Rats, and Humans

Sharma,

Burgers,

Beltman

2023

Pharmaceutics

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Nitrofurantoin (NFT) is a commonly used antibiotic for the treatment of urinary tract infections that can cause liver toxicity. Despite reports of hepatic adverse events associated with NFT exposure, there is still limited understanding of the interplay between NFT exposure, its disposition, and the risk of developing liver toxicity. In this study, we aim to develop a physiologically based pharmacokinetic (PBPK) model for NFT in three different species (rabbits, rats, and humans) that can be used as a standard tool for predicting drug-induced liver injury (DILI). We created several versions of the PBPK model using previously published kinetics data from rabbits, and integrated enterohepatic recirculation (EHR) using rat data. Our model showed that active tubular secretion and reabsorption in the kidney are critical in explaining the non-linear renal clearance and urine kinetics of NFT. We subsequently extrapolated the PBPK model to humans. Adapting the physiology to humans led to predictions consistent with human kinetics data, considering a low amount of NFT to be excreted into bile. Model simulations predicted that the liver of individuals with a moderate-to-severe glomerular filtration rate (GFR) is exposed to two-to-three-fold higher concentrations of NFT than individuals with a normal GFR, which coincided with a substantial reduction in the NFT urinary concentration. In conclusion, people with renal insufficiency may be at a higher risk of developing DILI due to NFT exposure, while at the same time having a suboptimal therapeutic effect with a high risk of drug resistance. Our PBPK model can in the future be used to predict NFT kinetics in individual patients on the basis of characteristics like age and GFR.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Extrapolation Of Pbpk Model From Rats and Rabbits To Humansmentioning

confidence: 99%

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Development of a Physiologically Based Pharmacokinetic Model for Nitrofurantoin in Rabbits, Rats, and Humans

Sharma,

Burgers,

Beltman

2023

Pharmaceutics

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High–performance liquid chromatographic determination of nitrofurantoin in plasma

Mandal

1993

J Clin Pharm Ther

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SUMMARY A reversed–phase high–performance liquid chromatographic method for the analysis of nitrofurantoin in rabbit plasma was developed. Acetanilide was used as the internal standard. The chromatography was performed using a C–18 column; the mobile phase consisted of 75:25 water to methanol; a flow rate of 09 ml/min; and UV detection at 270 run. Retention times were 58 and 101 min for nitrofurantoin and acetanilide, respectively. Recovery of nitrofurantoin added to plasma in the concentration range of 005–5 μg/ml was found to be greater than 92%. This procedure was used for the analysis of plasma samples collected over time following the oral administration of nitrofurantoin tablets to rabbits.

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Segmental Differences in Drug Permeability, Esterase Activity and Ketone Reductase Activity in the Albino Rabbit Intestine

Narawane

Podder

Bundgaard

et al. 1993

Journal of Drug Targeting

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Possible segmental differences in drug permeability as well as esterase and ketone reductase activities in the albino rabbit intestine were investigated. Beta adrenergic antagonists and timolol prodrugs spanning four orders of magnitude in distribution coefficient were used as model drugs. Drug penetration was evaluated in Ussing chambers using isolated segments of the duodenum, jejunum, ileum, ascending colon, descending colon, and rectum. Esterase and ketone reductase activities were determined in homogenates of the above segments using timolol ester prodrugs and levobunolol as substrates, respectively. The results indicate that the hydrophilic beta adrenergic antagonists atenolol and sotalol and moderately lipophilic metoprolol penetrated all intestinal segments equally well, whereas moderately lipophilic timolol and lipophilic propranolol, levobunolol and betaxolol were better absorbed from the large than from the small intestinal segments. Changes in lipophilicity exerted a more pronounced effect on the penetration of beta adrenergic antagonists in the large than the small intestinal segments. A similar pattern existed for timolol prodrugs. In addition to segmental differences in drug permeability, segmental differences in esterase and ketone reductase activities also existed. The level of esterase and ketone reductase activities in the small intestinal segments was, on average, 12 times and 5 times higher, respectively, than in the large intestinal segments. The implication of the above findings is that segmental differences in drug permeability and metabolism must be considered in the design of oral drug delivery systems.

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Absorption of orally, intraduodenally, and intraileally administered nitrofurantoin in man

Cited by 3 publications

References 5 publications

Development of a Physiologically Based Pharmacokinetic Model for Nitrofurantoin in Rabbits, Rats, and Humans

Development of a Physiologically Based Pharmacokinetic Model for Nitrofurantoin in Rabbits, Rats, and Humans

High–performance liquid chromatographic determination of nitrofurantoin in plasma

Segmental Differences in Drug Permeability, Esterase Activity and Ketone Reductase Activity in the Albino Rabbit Intestine

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