Transporter-Mediated Drug-Drug Interactions and Their Significance

Liu, Xiaodong

doi:10.1007/978-981-13-7647-4_5

Cited by 90 publications

(80 citation statements)

References 249 publications

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“…In conclusion, our results suggest that elevated pimozide blood levels observed when the drug is administered in combination with sertraline and/or aripiprazole can be explained at least in part by interaction at P-gp. Recently, there have been many reports on transporter-mediated drug-drug interactions [ 30 , 31 ], but only a few reports have described deaths that might have been due to transporter-mediated drug-drug interactions in the gastrointestinal tract. It is important to consider the potential risk of drug hyperabsorption due to drug-drug interactions mediated by efflux transporters in the gastrointestinal tract.…”

Section: Discussionmentioning

confidence: 99%

Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein

et al. 2020

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Drug-drug interaction was suggested to have played a role in the recent death due to cardiac arrest of a patient taking pimozide, sertraline and aripiprazole antipsychotic/antidepressant combination therapy. Here, we investigated the possible involvement of P-glycoprotein (P-gp)-mediated interaction among these drugs, using in vitro methods. ATPase assay confirmed that pimozide is a P-gp substrate, and might act as a P-gp inhibitor at higher concentrations. The maximum transport rate ( J max ) and half-saturation concentration ( K t ) for the carrier-mediated transport estimated by means of pimozide efflux assay using P-gp-overexpressing LLC-GA5-CoL150 cells were 84.9 ± 8.9 pmol/min/mg protein, and 10.6 ± 4.7 μM, respectively. These results indicate that pimozide is a good P-gp substrate, and it appears to have the potential to cause drug-drug interactions in the digestive tract at clinically relevant gastrointestinal concentrations. Moreover, sertraline or aripiprazole significantly decreased the efflux ratio of pimozide in LLC-GA5-CoL150 cells. Transport studies using Caco-2 cell monolayers were consistent with the results in LLC-GA5-CoL150 cells, and indicate that P-gp-mediated drug-drug interaction may occur in the gastrointestinal tract. Thus, P-gp inhibition by sertraline and/or aripiprazole may increase the gastrointestinal permeability of co-administered pimozide, resulting in an increased blood concentration of pimozide, which is known to be associated with an increased risk of QT prolongation, a life-threatening side effect.

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Section: Discussionmentioning

confidence: 99%

Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein

et al. 2020

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“…In fact, there are a variety of factors that are associated with the metabolism of various drugs. For instance, P-gp is an important protein that related to the transport of various drugs and UDP-glucuronosyltransferases were considered to mediate the biotransformation of several xenobiotics, of which the activity also induced changes in the plasma concentration of drugs (Liu 2019b , 2019a ). Therefore, the activity of these proteins and enzymes in the presence of anemarsaponin BII should be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Anemarsaponin BII inhibits the activity of CYP3A4, 2D6, and 2E1 with human liver microsomes

Wang

Jiang

Zhou

et al. 2020

Pharmaceutical Biology

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Context Anemarsaponin BII is one of the most active saponins isolated from Anemarrhena asphodeloides Bunge (Asparagaceae), a commonly used Chinese traditional paediatric medicine. Objective This study investigates the effects of anemarsaponin BII on the activity of CYP450s to provide more guidance for the clinical use of anemarsaponin BII. Materials and methods Using various diagnostic substrates, the effects of a fixed concentration of anemarsaponin BII (100 μM) on the activity of eight main isoforms of CYP450s (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6 and 2E1) was first studied with pooled human liver microsomes (HLMs). Then, dose-dependent (0, 2.5, 5, 10, 25, 50 and 100 μM anemarsaponin BII) and time-dependent (0, 5, 10, 15 and 30 min) experiments were performed to obtain corresponding kinetic parameters. Results Anemarsaponin BII showed significant inhibitory effects on the activity of CYP3A4, 2D6 and 2E1 with the IC 50 values of 13.67, 16.26 and 19.72 μM. Anemarsaponin BII acted as a non-competitive inhibitor of CYP3A4 with the K I value of 6.72 μM and competitive inhibitors of CYP2D6 and 2E1 with the K I values of 8.26 and 9.82 μM, respectively. Additionally, the inhibition of CYP3A4 was revealed to be time-dependent with the K I value of 4.88 μM and the K inact value of 0.053/min. Conclusions The inhibitory effect of anemarsaponin BII on the activity of CYP3A4, 2D6 and 2E1 indicated the potential drug–drug interaction between anemarsaponin BII and drugs metabolized by these CYP450s. Further in vivo experiments are needed to validate the potential drug–drug interactions.

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“…Transporters are now well-recognised as playing a major role in the different steps of pharmacokinetics, including intestinal absorption, distribution across blood-tissue barriers and biliary and renal elimination (Ayrton and Morgan, 2001;Konig et al, 2013). Inhibition of their activity by some drugs, called « perpetrators », can cause drug-drug interactions due to altered pharmacokinetics profile of co-administrated drugs substrates for the inhibited transporters and termed « victims » (Liu, 2019). This may also triggers adverse toxic effects, due to inhibition of endogenous substrate transport (Nigam, 2015).…”

Section: Introductionmentioning

confidence: 99%

Differential interactions of carbamate pesticides with drug transporters

et al. 2020

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1. Pesticides are now recognised to interact with drug transporters, but only few data are available on this issue for carbamate pesticides, a widely-used class of agrochemicals, to which humans are highly exposed. The present study was therefore designed to determine whether four representative carbamate pesticides, i.e., the insecticides aminocarb and carbofuran, the herbicide chlorpropham and the fungicide propamocarb, may impair activities of main drug transporters implicated in pharmacokinetics. 2. The interactions of carbamates with solute carrier and ATP-binding cassette transporters were investigated using cultured transporter-overexpressing cells, reference substrates and spectrofluorimetry-, liquid chomatography/tandem mass spectrometry-or radioactivity-based methods. 3. Aminocarb and carbofuran exerted no or minimal effects on transporter activities, whereas chlorpropham inhibited BCRP and OAT3 activities and propamocarb decreased those of OCT1 and OCT2, but cis-stimulated that of MATE2-K. Such alterations of transporters however required chlorpropham/propamocarb concentrations in the 5-50 µM range, likely not relevant to environmental exposure. Trans-stimulation assays and propamocarb accumulation experiments additionally suggested that propamocarb is not a substrate for OCT1, OCT2 and MATE2-K. 4. These data indicate that some carbamate pesticides can interact in vitro with some drug transporters, but only when used at concentrations higher than those expected to occur in environmentally-exposed humans.

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Transporter-Mediated Drug-Drug Interactions and Their Significance

Cited by 90 publications

References 249 publications

Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein

Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein

Anemarsaponin BII inhibits the activity of CYP3A4, 2D6, and 2E1 with human liver microsomes

Differential interactions of carbamate pesticides with drug transporters

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