Characterization of gastrointestinal absorption of digoxin involving influx and efflux transporter in rats: application of<i>mdr1a</i>knockout (−/−) rats into absorption study of multiple transporter substrate

Suzuki, Motoya; Kono, Hiroshi; Yoshikawa, Tomonori; Enya, Seiji; Nagao, Akemi; Takubo, Hiroaki; Kogayu, Motohiro

doi:10.3109/00498254.2014.920551

Cited by 8 publications

(6 citation statements)

References 44 publications

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“…The role of intestinal transporters in the active uptake and efflux of drugs has been of increasing interest with growing knowledge of the expression, regulation, and activity of transporters . GLY is reported to be a substrate for rat P-gp as well as OATP, − and the regional expression and activity of these transporters were included in the rat intestinal absorption model as described previously and in methods. For the in-house datasets, it was found that a decrease in the OATP activity improved the EOC of the predicted C – t profile.…”

Section: Discussionmentioning

confidence: 99%

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

et al. 2022

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Oral drug absorption is known to be impacted by the physicochemical properties of drugs, properties of oral formulations, and physiological characteristics of the intestine. The goal of the present study was to develop a mathematical model to predict the impact of particle size, feeding time, and intestinal transporter activity on oral absorption. A previously published rat continuous intestine absorption model was extended for solid drug absorption. The impact of active pharmaceutical ingredient particle size was evaluated with glyburide (GLY) as a model drug. Two particle size suspensions of glyburide were prepared with average particle sizes of 42.7 and 4.1 μm. Each suspension was dosed as a single oral gavage to male Sprague Dawley rats, and concentration–time (C–t) profiles of glyburide were measured with liquid chromatography coupled with tandem mass spectrometry. A continuous rat intestine absorption model was extended to include drug dissolution and was used to predict the absorption kinetics of GLY depending on particle size. Additional literature datasets of rat GLY formulations with particle sizes ranging from 0.25 to 4.0 μm were used for model predictions. The model predicted reasonably well the absorption profiles of GLY based on varying particle size and varying feeding time. The model predicted inhibition of intestinal uptake or efflux transporters depending on the datasets. The three datasets used formulations with different excipients, which may impact the transporter activity. Model simulations indicated that the model provides a facile framework to predict the impact of transporter inhibition on drug C–t profiles. Model simulations can also be conducted to evaluate the impact of an altered intestinal lumen environment. In conclusion, the rat continuous intestine absorption model may provide a useful tool to predict the impact of varying drug formulations on rat oral absorption profiles.

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Section: Discussionmentioning

confidence: 99%

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

et al. 2022

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“…DGX is not only a substrate of P-gp, but also a substrate of an intestinal uptake transporter, Oatp1a5 [ 21 ]. In this study, the expression of Oatp1a5 might have been altered by CPT-11 treatment to affect the absorption of DGX.…”

Section: Discussionmentioning

confidence: 99%

Digoxin absorption decreased independently of P-gp activity in rats with irinotecan-induced gastrointestinal damage

Tsuchitani

Akiyoshi

Imaoka

et al. 2021

J Pharm Health Care Sci

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Background Irinotecan (CPT-11) is clinically known to cause severe diarrhea and gastrointestinal damage. Recently, we have reported that CPT-11-induced gastrointestinal damage is associated with the upregulation of intestinal P-glycoprotein (P-gp) expression and decreased absorption of its substrate, dabigatran etexilate (DABE), using a rat model. However, the P-gp activity or its contribution to the decreased absorption remains unclear. The aim of this study was to quantitatively evaluate how P-gp activity changes in rats with CPT-11-induced gastrointestinal damage, as assessed by the absorption of digoxin (DGX), a typical P-gp substrate. Methods Male Sprague-Dawley rats were intravenously administered CPT-11 at a dose of 60 mg/kg/day for 4 days to induce gastrointestinal damage. Then, the rats were administered DGX orally (40 μg/kg), after some of them were orally administered clarithromycin (CAM; 10 mg/kg), a P-gp inhibitor. DGX (30 μg/kg) was administered intravenously to determine the bioavailability (BA). The rats’ DGX plasma concentration profiles were determined using LC-MS/MS. Results CPT-11 treatment decreased the maximum concentration (Cmax) and area under the plasma concentration-time curve (AUCpo) of DGX, which does not contradict to the DABE study. Although in the CPT-11-treated group the BA of DGX was significantly decreased to 40% of the control value, CAM did not affect the BA of DGX in the CPT-11-treated group. Conclusions Increased P-gp expression in rats with CPT-11-induced gastrointestinal damage is not necessarily associated with increased P-gp activity or contribution to the drug absorption in vivo. The decreased DGX absorption observed in this study might be attributable to other factors, such as a reduction in the absorptive surface area of the gastrointestinal tract.

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“…DIG is known to be a P-gp substrate, whereas GLY relies on both Oatp and P-gp (El-Kattan and Varma, 2012;Estudante et al, 2013;Suzuki et al, 2014). Presence of food is reported to inhibit Oatp2b1, leading to PK differences between fasted and fed groups (Lee et al, 2020).…”

Section: Velocity Vel(x)mentioning

confidence: 99%

“…DIG is BCS class 4 and a P-glycoprotein (P-gp) substrate. GLY is BCS class 2 and a P-gp and organic anion transporter protein (Oatp) substrate (El-Kattan and Varma, 2012;Estudante et al, 2013;Suzuki et al, 2014). All datasets were collected at various feeding times postdose.…”

Section: Introductionmentioning

confidence: 99%

Predicting Impact of Food and Feeding Time on Oral Absorption of Drugs with a Novel Rat Continuous Intestinal Absorption Model

2022

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Intricacies in intestinal physiology, drug properties, and food effects should be incorporated into models to predict complex oral drug absorption. A previously published human continuous intestinal absorption model based on the convection-diffusion equation was modified specifically for the male Sprague-Dawley rat in this report. Species-specific physiologic conditions along intestinal lengthexperimental velocity and pH under fasted and fed conditions, were measured and incorporated into the intestinal absorption model. Concentration-time (C-t) profiles were measured upon a single intravenous and peroral (PO) dose for three drugs: amlodipine (AML), digoxin (DIG), and glyburide (GLY). Absorption profiles were predicted and compared with experimentally collected data under three feeding conditions: 12-hour fasted rats were provided food at two specific times after oral drug dose (1 hour and 2 hours for AML and GLY; 0.5 hours and 1 hour for DIG), or they were provided food for the entire study. Intravenous versus PO C-t profiles suggested absorption even at later times and informed design of appropriate mathematical input functions based on experimental feeding times. With this model, AML, DIG, and GLY oral C-t profiles for all feeding groups were generally well predicted, with exposure overlap coefficients in the range of 0.80-0.97. Efflux transport for DIG and uptake and efflux transport for GLY were included, modeling uptake transporter inhibition in the presence of food. Results indicate that the continuous intestinal rat model incorporates complex physiologic processes and feeding times relative to drug dose into a simple framework to provide accurate prediction of oral absorption. SIGNIFICANCE STATEMENTA novel rat continuous intestinal model predicts drug absorption with respect to time and intestinal length. Feeding time relative to dose was modeled as a key effect. Experimental fasted/fed intestinal pH and velocity, efflux and uptake transporter expression along intestinal length, and uptake transporter inhibition in the presence of food were modeled. The model uses the pharmacokinetic profiles of three model drugs and provides a novel framework to study food effects on absorption.

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Characterization of gastrointestinal absorption of digoxin involving influx and efflux transporter in rats: application ofmdr1aknockout (−/−) rats into absorption study of multiple transporter substrate

Cited by 8 publications

References 44 publications

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

Digoxin absorption decreased independently of P-gp activity in rats with irinotecan-induced gastrointestinal damage

Predicting Impact of Food and Feeding Time on Oral Absorption of Drugs with a Novel Rat Continuous Intestinal Absorption Model

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