Intestinal efflux transporters and drug absorption

Murakami, Teruo; Takano, Mikihisa

doi:10.1517/17425255.4.7.923

Cited by 182 publications

(99 citation statements)

References 99 publications

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“…In fact, estrone-3-sulfate is a well known substrate for most of the intestinal transporters shown in Figure 1, for example OATP1A2, OATP2B1, BCRP and MRP2 (Table 2), that are currently regarded as the most likely clinical relevant transporters for DDIs in the intestinal tract apart from P-gp. [8][9][10] Multiple transporters at play Caco-2 cells can be employed for the determination of Km or Ki/IC50 values for a specific transporter and for the overall assessment of the involvement of intestinal transporters in the absorptive process of a drug substance. However, in the former case, one should be extremely vigilant due to the lack of specificity of the probe substances and the involvement of several transporters in native cell systems.…”

Section: Limitations Of In-vitro Determined Kinetic Parameters For Trmentioning

confidence: 99%

“…However, an interest for other intestinal transporters is now emerging, in particular for transporters that preferably bind organic anions, especially the breast cancer resistance protein (BCRP), the multidrug resistance associated protein (MRP) 2, and the organic anion transporting polypeptides (OATP) 2B1 and 1A2. [8][9][10] Charged substances such as organic anions are more prone to rely on transporters for intestinal permeability because their passive transcellular route is generally reserved to uncharged substances (although the intestinal permeability of some ionized drugs may be driven by pH partition). [11] Hence, organic anions may become both victim drug and perpetrator drug of a transporter-mediated DDI.…”

Section: Introductionmentioning

confidence: 99%

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Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Grandvuinet

Vestergaard

Rapin³

et al. 2012

Journal of Pharmacy and Pharmacology

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Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in‐vitro methods presently employed in drug–drug interaction (DDI) investigations. Key findings Current knowledge on the intestinal expression of the apical sodium‐dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3‐5, the multidrug resistance associated proteins (MRP) 1–6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/β (OSTα/β) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in‐vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in‐vitro parameters for transporters (Km/Ki/IC50, efflux ratio). The applicability of using a cut‐off value (estimated based on the intestinal drug concentration divided by the Ki or IC50) has also been considered. Summary A re‐evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P‐glycoprotein. Moreover, the interplay between various processes that a drug is subject to in‐vivo such as translocation by several transporters and dissolution should be considered.

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Section: Limitations Of In-vitro Determined Kinetic Parameters For Trmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Grandvuinet

Vestergaard

Rapin³

et al. 2012

Journal of Pharmacy and Pharmacology

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“…These transporters are well known for their ability to limit the bioavailability of pharmaceutical agents and evidence suggests that several clinically relevant food-drug interactions occur because of the ability of some food components to either upregulate or inhibit the efflux pumps, causing reduced drug bioavailability and efficacy, or higher absorption and possible toxic side effects, respectively (reviewed in detail in [56]). These are discussed in greater detail in ''Polyphenols as transporter substrates'' below.…”

Section: Absorption Metabolism and Distribution Of Polyphenolsmentioning

confidence: 99%

“…Likewise, quercetin has very limited bioavailability through gut epithelia and regardless of the amount consumed orally, plasma concentrations of quercetin rarely exceed 1 lM. Although not specifically proven, this is likely to be at least in part due to BCRP expression in gut epithelia (see [56] for review).…”

Section: Polyphenols As Abc Transporter Substratesmentioning

confidence: 99%

Improving the oral bioavailability of beneficial polyphenols through designed synergies

2009

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“…Due to its location in the apical or brush border membrane of enterocytes, MDR1 can have a great impact on the bioavailability of certain drugs [35,[83][84][85]. Consequently, MDR1…”

Section: Mdr1 (Abcb1)mentioning

confidence: 99%

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Stieger

Meier

2011

Pharmacogenomics

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This article summarizes the impact of the pharmacogenetics of drug transporters expressed in the enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. The role of pharmacogenetics in the function of drug transporter proteins in vitro is now well established and evidence is rapidly accumulating from in vivo pharmacokinetic studies, which suggests that genetic variants of drug transporter proteins can translate into clinically relevant phenotypes. However, a large amount of conflicting information on the clinical relevance of drug transporter proteins has so far precluded the emergence of a clear picture regarding the role of drug transporter pharmacogenetics in medical practice. This is very well exemplified by the case of P-glycoprotein (MDR1, ABCB1). The challenge is now to develop pharmacogenetic models with sufficient predictive power to allow for translation into drug therapy. This will require a combination of pharmacogenetics of drug transporters, drug metabolism and pharmacodynamics of the respective drugs.

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Intestinal efflux transporters and drug absorption

Cited by 182 publications

References 99 publications

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Improving the oral bioavailability of beneficial polyphenols through designed synergies

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

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