Intestinal drug transporters: An overview

Estudante, Margarida; Morais, José; Soveral, Graça; Benet, Leslie Z.

doi:10.1016/j.addr.2012.09.042

Cited by 273 publications

(207 citation statements)

References 200 publications

Supporting

Mentioning

198

Contrasting

Unclassified

Order By: Relevance

“…Hence, increased Pgp expression can lead to increased clearance of these ARVs from intestinal tissue in ARTtreated HIV ϩ patients and will likely decrease their intracellular accumulation in enterocytes and permeativity across the intestinal epithelium. In addition, we observed that some ART-treated subjects had higher transcriptional expression of several drug uptake transporters (OCT1, OAT1, OATP1A2, ENT1, and ENT2), which could potentially compensate for the adverse effect of increased drug efflux and/or metabolism of common drug substrates such as PIs (substrates of organic anion transporting polypeptides (16,(34)(35)(36). Due to limited tissue availability, in this study we did not evaluate protein expression of these drug uptake transporters.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

Kis

Sankaran-Walters

Hoque

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

؉ ART-naive group than in uninfected subjects. qPCR analysis confirmed significantly lower expression of ABCC2/MRP2 in ART-naive subjects than in the control group, while CYP3A4 and ABCG2/BCRP showed a trend toward decreased expression. Protein expression of MRP2 and BCRP was also significantly lower in the HIV ؉ naive group than in the control group and was partially restored to baseline levels in HIV ؉ subjects receiving ART. In contrast, gene and protein expression of ABCB1/Pgp was significantly increased in HIV ؉ subjects on ART relative to HIV ؉ ART-naive subjects. These data demonstrate that the expression of drug-metabolizing enzymes and efflux transporters is significantly altered in therapy-naive HIV ؉ subjects and in those receiving ART. Since CYP3A4, Pgp, MRPs, and BCRP metabolize or transport many antiretroviral drugs, their altered expression with HIV infection may negatively impact drug pharmacokinetics in HIV ؉ subjects. This has clinical implications when using data from healthy volunteers to guide ART.

show abstract

Section: Discussionmentioning

confidence: 99%

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

Kis

Sankaran-Walters

Hoque

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…There are reports of some proteins that are capable of transporting creatinine in the kidney, notably OAT2 (Lepist et al, 2014). However, expression of OAT2 is either low or absent in the intestine (Maubon et al, 2007;Meier et al, 2007;Estudante et al, 2013), and creatinine absorption in the intestine has generally been ascribed to the paracellular pathway (Dominguez and Pomerene, 1945;Pappenheimer, 1990;Turner et al, 2000). In addition, we tested for saturation kinetics of intestinal creatinine absorption (see 'Validation of paracellular probes', below).…”

Section: Assessment Of Paracellular Absorption In Intact Animalsmentioning

confidence: 99%

Paracellular nutrient absorption is higher in bats than rodents: integrating from intact animals to the molecular level

Price

Rott

Caviedes‐Vidal

et al. 2014

Journal of Experimental Biology

View full text Add to dashboard Cite

Flying vertebrates have been hypothesized to rely heavily on paracellular absorption of nutrients to compensate for having smaller intestines than non-flyers. We tested this hypothesis in an insectivorous bat (Myotis lucifugus) and two insect-eating rodents (Onychomys leucogaster and Peromyscus leucopus). In intact animals, the fractional absorption of orally dosed L-arabinose (M r 150) was 82% in M. lucifugus, which was more than twice that of the rodents. Absorption of creatinine (M r 113) was greater than 50% for all species and did not differ between M. lucifugus and the rodents. We also conducted intestinal luminal perfusions on anesthetized animals. Absorption of L-arabinose per nominal surface area in M. lucifugus was nearly double that of the rodents, while absorption of creatinine was not different among species. Using an everted sleeve preparation, we demonstrated that high concentrations of L-arabinose and creatinine did not inhibit their own uptake, validating their use as passive, paracellular probes. Histological measurements indicated that M. lucifugus has more cells, and presumably more tight junctions, per nominal surface area than P. leucopus. This seems unlikely to explain entirely the higher absorption of L-arabinose in M. lucifugus during perfusions, because L-arabinose absorption normalized to the number of enterocytes was still double that of P. leucopus. As an alternative, we investigated tight junction gene expression. M. lucifugus had higher expression of claudin-1 and claudin-15, and lower expression of claudin-2 relative to P. leucopus. Expression of claudin-7 and occludin did not differ among species. Taken together, our results support the hypothesis that bats have evolved higher paracellular nutrient absorption than non-flying animals, and that this phenomenon might be driven by both histological characteristics and differences in tight junction gene expression.

show abstract

“…The most commonly investigated ABC family transporters are P-gp, multidrug resistance-associated protein 2 (MRP2) and BCRP. 25,26) Substrates of MRP2 are glutathione, glucuronide sulfate, heavy metal conjugates, and unconjugated organic anions, 26) therefore P-gp and BCRP are more likely to be involved in the efflux of YQA-14. These potential transporters, as involved in the efflux of YQA-14, were further characterized in our study.…”

Section: Discussionmentioning

confidence: 99%

P-Glycoprotein (ABCB1) Limits the Brain Distribution of YQA-14, a Novel Dopamine D<sub>3</sub> Receptor Antagonist

Liu

Wang

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

YQA-14 is a promising agent for treating addiction to cocaine and opioids. However, previous studies have showed there is marked contrast between the relatively small differences in pharmacological action in vivo and the large differences in their respective receptor binding properties in vitro. We hypothesized that the conflict between the in vivo and in vitro outcomes was attributable to poor brain exposure to YQA-14 caused by drug efflux transporters. To address this issue, we investigated the directional flux of YQA-14 across Caco-2 cells at 37°C or 4°C and the bidirectional transport in the presence and absence of transporter chemical inhibitors. These phenomena were further investigated by an in vivo determination of the brain and blood pharmacokinetics (PK) profile of YQA-14 following intraperitoneal administration with and without inhibitor. The efflux ratio of YQA-14 on Caco-2 cell monolayers was 2.39 and the efflux was temperaturedependent. When co-incubated with GF120918 or LY335979, the efflux of YQA-14 was markedly decreased. However, there was no significant difference in the permeability of YQA-14 when the cells were treated with Ko143. In vivo experiments showed that the brain-to-plasma ratio increased by more than 75-fold and 20-fold with co-administration of GF120918 and LY335979, respectively. Use of Ko143 did not change the brain-toblood ratio of YQA-14. The results indicate that the brain distribution of YQA-14 was restricted because of active efflux transport at the blood brain barrier. In addition, P-glycoprotein (P-gp) played a dominant role in limiting the distribution of YQA-14 to the brain.

show abstract

Intestinal drug transporters: An overview

Cited by 273 publications

References 200 publications

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

Paracellular nutrient absorption is higher in bats than rodents: integrating from intact animals to the molecular level

P-Glycoprotein (ABCB1) Limits the Brain Distribution of YQA-14, a Novel Dopamine D<sub>3</sub> Receptor Antagonist

Contact Info

Product

Resources

About