Roles of P-glycoprotein and multidrug resistance protein in transporting para-aminosalicylic acid and its N-acetylated metabolite in mice brain

Hong, Liping; Xu, Cong; O’Neal, Stefanie L.; Bi, Huichang; Huang, Min; Zheng, Wei; Zeng, Su

doi:10.1038/aps.2014.103

Cited by 19 publications

(9 citation statements)

References 42 publications

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“…4). Despite the results of a previous study indicating that inhibition of P-gp efflux caused an increased PAS concentration in the brain (22,23), our in vitro transport data found no involvement of P-gp in PAS transport. The half-life of orally administered PAS is reported to be 1.5 to 2 h, with the concentration remaining in plasma within 4 to 5 h after administration of a single conventional dose being negligible.…”

Section: Discussioncontrasting

confidence: 99%

Evaluation of para -Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

Parvez

Shin

Jung

et al. 2017

Antimicrob Agents Chemother

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para-Aminosalicylic acid (PAS) is a second-line antituberculosis drug that has been used to treat multidrug-resistant and extensively drug-resistant tuberculosis for more than 60 years. Renal secretion and glomerular filtration are the major pathways for the elimination of PAS. We comprehensively studied PAS transport by using cell lines that overexpressed various transporters and found that PAS acts as a novel substrate of an organic anionic polypeptide (OATP1B1), organic cationic transporters (OCT1 and OCT2), and organic anion transporters (OAT1 and OAT3) but is not a substrate of any ATP-binding cassette (ABC) transporters. Net PAS uptake was measured, and the transport affinities (K m values) for OATP1B1, OCT1, OCT2, OAT1, and OAT3 were found to be 50.0, 20.3, 28.7, 78.1, and 100.1 M, respectively. The net uptake rates suggested that renal OAT1 and OAT3 play relatively major roles in PAS elimination. The representative inhibitors rifampin for OATP1B1, probenecid for OAT1 and OAT3, and verapamil for OCT1 and OCT2 greatly inhibited PAS uptake, suggesting that PAS is dependent on multiple transporters for uptake. We also evaluated nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), and metformin for the inhibition of PAS uptake via these transporters. Half-maximal (50%) inhibitory concentrations (IC 50 s) were kinetically determined and used to predict the drug-drug interactions (DDIs) affecting these transporters' activity toward PAS. We found that rifampin, probenecid, ibuprofen, naproxen, cimetidine, and quinidine each exhibited a significant potential for in vivo DDIs with PAS. In this study, PAS was found to be a novel substrate of several transporters, and drugs that inhibit these transporters can reduce PAS elimination.

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Section: Discussioncontrasting

confidence: 99%

Evaluation of para -Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

Parvez

Shin

Jung

et al. 2017

Antimicrob Agents Chemother

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“…Both PAS and AcPAS were transported in the brain by the multidrug resistance-associated protein 1 (MRP1), a member of the superfamily of ATP-binding cassette (ABC) transporters. However, the removal or efflux of PAS from brain parenchyma into the blood was mediated by the multidrug resistance protein 1 (MDR1), also called P-glycoprotein [136]. …”

Section: Diagnosis and Clinical Interventionmentioning

confidence: 99%

Manganese Toxicity Upon Overexposure: a Decade in Review

O’Neal

Zheng

2015

Curr Envir Health Rpt

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647

340

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Exposure to manganese (Mn) causes clinical signs and symptoms resembling, but not identical to, Parkinson’s disease. Since our last review on this subject in 2004, the past decade has been a thriving period in the history of Mn research. This report provides a comprehensive review on new knowledge gained in the Mn research field. Emerging data suggest that beyond traditionally recognized occupational manganism, Mn exposures and the ensuing toxicities occur in a variety of environmental settings, nutritional sources, contaminated foods, infant formulas, and water, soil, and air with natural or man-made contaminations. Upon fast absorption into the body via oral and inhalation exposures, Mn has a relatively short half-life in blood, yet fairly long half-lives in tissues. Recent data suggest Mn accumulates substantially in bone, with a half-life of about 8–9 years expected in human bones. Mn toxicity has been associated with dopaminergic dysfunction by recent neurochemical analyses and synchrotron X-ray fluorescent imaging studies. Evidence from humans indicates that individual factors such as age, gender, ethnicity, genetics, and pre-existing medical conditions can have profound impacts on Mn toxicities. In addition to body fluid-based biomarkers, new approaches in searching biomarkers of Mn exposure include Mn levels in toenails, non-invasive measurement of Mn in bone, and functional alteration assessments. Comments and recommendations are also provided with regard to the diagnosis of Mn intoxication and clinical intervention. Finally, several hot and promising research areas in the next decade are discussed.

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“…P-gp was an important factor contributing to the occurrence of DDI [ 23 ], so it was necessary to evaluate whether the investigational drug was an inhibitor of P-gp. From Figure 3 , we observed that Dl0410 could inhibit the transport of Rho123 from the BL side to the AL side in MDCK-MDR1 cells, indicating that it was a substrate as well as an inhibitor of P-gp.…”

Section: Discussionmentioning

confidence: 99%

Effects of P-Glycoprotein on the Transport of DL0410, a Potential Multifunctional Anti-Alzheimer Agent

et al. 2017

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In our study, we attempted to investigate the influences of P-glycoprotein (P-gp) on DL0410, a novel synthetic molecule for Alzheimer’s disease (AD) treatment, for intestinal absorption and blood-brain barrier permeability in vitro and related binding mechanisms in silico. Caco-2, MDCK, and MDCK-MDR1 cells were utilized for transport studies, and homology modelling of human P-gp was built for further docking study to uncover the binding mode of DL0410. The results showed that the apparent permeability (Papp) value of DL0410 was approximately 1 × 10−6 cm/s, indicating the low permeability of DL0410. With the presence of verapamil, the directional transport of DL0410 disappeared in Caco-2 and MDCK-MDR1 cells, suggesting that DL0410 should be a substrate of P-gp, which was also confirmed by P-gp ATPase assay. In addition, DL0410 could competitively inhibit the transport of Rho123, a P-gp known substrate. According to molecular docking, we also found that DL0410 could bind to the drug binding pocket (DBP), but not the nucleotide binding domain (NBD). In conclusion, DL0410 was a substrate as well as a competitive inhibitor of P-gp, and P-gp had a remarkable impact on the intestine and brain permeability of DL0410, which is of significance for drug research and development.

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Roles of P-glycoprotein and multidrug resistance protein in transporting para-aminosalicylic acid and its N-acetylated metabolite in mice brain

Cited by 19 publications

References 42 publications

Evaluation of para -Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

Evaluation of para -Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

Manganese Toxicity Upon Overexposure: a Decade in Review

Effects of P-Glycoprotein on the Transport of DL0410, a Potential Multifunctional Anti-Alzheimer Agent

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