The Impact of Intestinal Failure on Oral Drug Absorption: A Review

Ward, Nicola

doi:10.1007/s11605-009-1151-9

Cited by 38 publications

(23 citation statements)

References 30 publications

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“…In order to be physiologically effective, orally administered drugs must first be absorbed by the body, a process which occurs largely in the small intestines [2,3]. …”

Section: Introductionmentioning

confidence: 99%

Improvement of paracellular transport in the Caco-2 drug screening model using protein-engineered substrates

et al. 2017

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The Caco-2 assay has achieved wide popularity among pharmaceutical companies in the past two decades as an in vitro method for estimation of in vivo oral bioavailability of pharmaceutical compounds during preclinical characterization. Despite its popularity, this assay suffers from a severe under-prediction of the transport of drugs which are absorbed paracellularly, that is, which pass through the cell-cell tight junctions of the absorptive cells of the small intestine. Here, we propose that simply replacing the collagen I matrix employed in the standard Caco-2 assay with an engineered matrix, we can control cell morphology and hence regulate the cell-cell junctions that dictate paracellular transport. Specifically, we use a biomimetic engineered extracellular matrix (eECM) that contains modular protein domains derived from two ECM proteins found in the small intestine, fibronectin and elastin. This eECM allows us to independently tune the density of cell-adhesive RGD ligands presented to Caco-2 cells as well as the mechanical stiffness of the eECM. We observe that lower amounts of RGD ligand presentation as well as decreased matrix stiffness results in Caco-2 morphologies that more closely resemble primary small intestinal epithelial cells than Caco-2 cells cultured on collagen. Additionally, these matrices result in Caco-2 monolayers with decreased recruitment of actin to the apical junctional complex and increased expression of claudin-2, a tight junction protein associated with higher paracellular permeability that is highly expressed throughout the small intestine. Consistent with these morphological differences, drugs known to be paracellularly transported in vivo exhibited significantly improved transport rates in this modified Caco-2 model. As expected, permeability of transcellularly transported drugs remained unaffected. Thus, we have demonstrated a method of improving the physiological accuracy of the Caco-2 assay that could be readily adopted by pharmaceutical companies without major changes to their current testing protocols.

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“…In order to be physiologically effective, orally administered drugs must first be absorbed by the body, a process which occurs largely in the small intestines [2,3]. …”

Section: Introductionmentioning

confidence: 99%

Improvement of paracellular transport in the Caco-2 drug screening model using protein-engineered substrates

et al. 2017

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“…Oral administration is the preferred route by patients due to its convenience, price, comfort, and handling 1 . The orally-administered drugs may undergo extensive first-pass metabolism in the gastro-intestinal tract, and this may result in limited systematic bioavailability, and decreased therapeutic effects 2 , 3 . Absorption of orally administered drugs takes place primarily in the small intestine, followed by delivery to the liver via the portal blood.…”

Section: Introductionmentioning

confidence: 99%

Characterizing drug-metabolizing enzymes and transporters that are bona fide CAR-target genes in mouse intestine

Shinhee

Cheng

Cui

2016

Acta Pharmaceutica Sinica B

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Intestine is responsible for the biotransformation of many orally-exposed chemicals. The constitutive androstane receptor (CAR/Nr1i3) is known to up-regulate many genes encoding drug-metabolizing enzymes and transporters (drug-processing genes/DPGs) in liver, but less is known regarding its effect in intestine. Sixty-day-old wild-type and Car−/− mice were administered the CAR-ligand TCPOBOP or vehicle once daily for 4 days. In wild-type mice, Car mRNA was down-regulated by TCPOBOP in liver and duodenum. Car−/− mice had altered basal intestinal expression of many DPGs in a section-specific manner. Consistent with the liver data (Aleksunes and Klaassen, 2012), TCPOBOP up-regulated many DPGs (Cyp2b10, Cyp3a11, Aldh1a1, Aldh1a7, Gsta1, Gsta4, Gstm1-m4, Gstt1, Ugt1a1, Ugt2b34, Ugt2b36, and Mrp2–4) in specific sections of small intestine in a CAR-dependent manner. However, the mRNAs of Nqo1 and Papss2 were previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine. Interestingly, many known CAR-target genes were highest expressed in colon where CAR is minimally expressed, suggesting that additional regulators are involved in regulating their expression. In conclusion, CAR regulates the basal expression of many DPGs in intestine, and although many hepatic CAR-targeted DPGs were bona fide CAR-targets in intestine, pharmacological activation of CAR in liver and intestine are not identical.

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“…159 Recognition that enteral absorption of drugs and supplements is erratic and inherently unpredictable has resulted in more use of other drug delivery platforms. 186 These include buccal, transdermal, and rectal applications. Transdermal clonidine has been shown to reduce diarrhea and sodium loss in patients with proximal jejunostomy.…”

Section: Maximizing Enteral Absorptionmentioning

confidence: 99%

Current Management of Short Bowel Syndrome

Thompson

Rochling

Weseman

et al. 2012

Current Problems in Surgery

111

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The Impact of Intestinal Failure on Oral Drug Absorption: A Review

Abstract: The input of specialist pharmacists is necessary in the management of these patients to ensure that appropriate drugs and formulations are prescribed in a timely manner to optimize absorption and resultant efficacy.

Cited by 38 publications

References 30 publications

Improvement of paracellular transport in the Caco-2 drug screening model using protein-engineered substrates

Improvement of paracellular transport in the Caco-2 drug screening model using protein-engineered substrates

Characterizing drug-metabolizing enzymes and transporters that are bona fide CAR-target genes in mouse intestine

Current Management of Short Bowel Syndrome

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