Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption

Hunter, Janice; Hirst, Barry H.

doi:10.1016/s0169-409x(97)00497-3

Cited by 255 publications

(145 citation statements)

References 134 publications

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“…Table 1 summarizes the MDR1 substrate drugs. [27][28][29][30][31][32] Generally speaking, drug transporters, e.g., MDR1 and drug metabolizing enzymes, e.g., cytochrome P450s (CYPs), are the two major biological factors determining the pharmacokinetics of drugs. It has been serendipitously noted that MDR1 and CYP3A4 share a significant overlap in substrate specificity.…”

Section: Mdr1 In Pharmacokinetics and Pharma-codynamicsmentioning

confidence: 99%

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Sakaeda

Nakamura

Okumura

2002

Biological & Pharmaceutical Bulletin

172

110

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The multidrug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily of membrane transporters. MDR1 acts as an energy-dependent efflux pump that exports its substrates out of cells. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multidrug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and detected 15 single nucleotide polymorphisms (SNPs). They also indicated that a polymorphism in exon 26 at position 3435 (C3435T), a silent mutation, affected the expression level of MDR1 protein in duodenum, and thereby the intestinal absorption of digoxin. To date, the genotype frequencies of C3435T have been investigated extensively using a larger population and interethnic difference has been elucidated, and a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on MDR1 genotype-related MDR1 expression and pharmacokinetics have also been performed around the world; however, results were not always consistent with Hoffmeyer's report. In this review, published reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping. In addition, recent investigations have raised the possibility that MDR1 and related transporters play a fundamental role in regulating apoptosis and immunology, and in fact, there are reports of MDR1-related susceptibility to inflammatory bowel disease, HIV infection and renal cell carcinoma. Herein, these issues are also summarized, and the current status of the knowledge in the area of pharmacogenomics of other transporters is briefly introduced.

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Section: Mdr1 In Pharmacokinetics and Pharma-codynamicsmentioning

confidence: 99%

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Sakaeda

Nakamura

Okumura

2002

Biological & Pharmaceutical Bulletin

172

110

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“…One of the key components of this barrier is P-glycoprotein (PGP), a member of the ABC transporter family (Hunter & Hirst, 1997), that is coded for by the MDR1 gene in humans and by the mdr1a and mdr1b genes in rodents, only mdr1a being found in intestine (Croop et al, 1989). PGP is a polyspeci®c transporter that can pump a very broad range of substrates, including vinca alkaloids, anthracyclines, digoxin, epipodophyllotoxins and b-adrenergic agonists, into the gut lumen (Hunter & Hirst, 1997). In vivo studies con®rm that PGP signi®cantly limits the oral bio-availability of several drugs (Fromm, 2000).…”

Section: Introductionmentioning

confidence: 99%

Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

Stephens

O’Neill

Bennett

et al. 2002

British J Pharmacology

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1 Intestinal xenobiotic transporters are a signi®cant barrier to the absorption of many orally administered drugs. P-glycoprotein (PGP) is the best known, but several others, including members of the multidrug resistance-associated protein (MRP) family, are also expressed. De®nitive information on their precise e ect on intestinal drug permeability is scarce due to a lack of speci®c inhibitors and the di culty of studying non-PGP activity in the presence of high PGP expression. 2 We have investigated the in vitro use of intestinal tissues from PGP knockout (mdr1a (7/7)) mice as a tool for dissecting the mechanisms of intestinal drug e ux. The permeability characteristics of digoxin (DIG), paclitaxel (TAX) and etoposide (ETOP) were measured in ileum from mdr1a (7/7) and wild-type (FVB) mice mounted in Ussing chambers. 3 DIG and TAX exhibited marked e ux across FVB tissues (B-A : A-B apparent permeability (P app ) ratio 10 and 17 respectively) which was absent in mdr1a (7/7) tissues, con®rming that PGP is the sole route of intestinal e ux for these compounds. The A-B P app of both compounds was 3 ± 5 fold higher in mdr1a (7/7) than in FVB. 4 Polarized transport of ETOP in FVB tissues was reduced but not abolished in mdr1a (7/7) tissues. Residual ETOP e ux in mdr1a (7/7) tissues was abolished by the MRP inhibitor MK571, indicating involvement of both PGP and MRP. 5 MK571 abolished calcein e ux in mdr1a (7/7) tissues, while quinidine had no parallel e ect in FVB tissues, suggesting involvement of MRP but not PGP. 6 Tissues from mdr1a (7/7) mice provide a novel approach for investigating the in¯uence of PGP ablation on intestinal permeability and for resolving PGP and non-PGP mechanisms that modulate drug permeability.

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“…rate of detoxification . Several mechanisms, such as efflux transporters, allow excretion of toxins in the feces, thereby decreasing concentrations of toxins in the blood (Hunter and Hirst 1997). For example, P-glycoproteins in the gut epithelial cells actively transport toxic compounds out of the gut cell and reduce delivery to circulation (Sparreboom et al 1997).…”

Section: Discussionmentioning

confidence: 99%

Modeling trade‐offs between plant fiber and toxins: a framework for quantifying risks perceived by foraging herbivores

Camp

Shipley

Johnson

et al. 2015

Ecology

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Abstract. When selecting habitats, herbivores must weigh multiple risks, such as predation, starvation, toxicity, and thermal stress, forcing them to make fitness trade-offs. Here, we applied the method of paired comparisons (PC) to investigate how herbivores make trade-offs between habitat features that influence selection of food patches. The method of PC measures utility and the inverse of utility, relative risk, and makes trade-offs and indifferences explicit by forcing animals to make choices between two patches with different types of risks. Using a series of paired-choice experiments to titrate the equivalence curve and find the marginal rate of substitution for one risk over the other, we evaluated how toxin-tolerant (pygmy rabbit Brachylagus idahoensis) and fiber-tolerant (mountain cottontail rabbit Sylviagus nuttallii ) herbivores differed in their hypothesized perceived risk of fiber and toxins in food. Pygmy rabbits were willing to consume nearly five times more of the toxin 1,8-cineole in their diets to avoid consuming higher levels of fiber than were mountain cottontails. Fiber posed a greater relative risk for pygmy rabbits than cottontails and cineole a greater risk for cottontails than pygmy rabbits. Our flexible modeling approach can be used to (1) quantify how animals evaluate and trade off multiple habitat attributes when the benefits and risks are difficult to quantify, and (2) integrate diverse risks that influence fitness and habitat selection into a single index of habitat value. This index potentially could be applied to landscapes to predict habitat selection across several scales.

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Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption

Cited by 255 publications

References 134 publications

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

Modeling trade‐offs between plant fiber and toxins: a framework for quantifying risks perceived by foraging herbivores

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