Enzyme-Transporter-Mediated Drug Interactions with Small Molecule Tyrosine Kinase Inhibitors

Shao, Jiahao; Markowitz, John S.; Bei, Di; An, Guohua

doi:10.1002/jps.24113

Cited by 37 publications

(44 citation statements)

References 224 publications

(449 reference statements)

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“…Indeed, when given with other drugs, TKIs may not only be the victims in drug interactions but also play a role as perpetrators influencing the pharmacokinetics of coadministered drugs. However, CYP3A4 interactions of TKIs as perpetrators currently appear to be generally modest …”

Section: Discussionmentioning

confidence: 99%

“…Moreover, polymorphism in influx transporters (eg, OCTN1, OCTN2, and OATP1A2) may play a role in the disposition and outcome of TKIs . Influx and efflux transporters play an increasing role in the field of oncology as a result of their contribution to interindividual variability in the pharmacokinetics as well as the clinical outcome of TKIs …”

Section: Polymorphismmentioning

confidence: 99%

“…Absorption can be reduced by coadministration of gastric acid–reducing agents with a rather complex mechanism. Increase or decrease in the systemic exposure can result from induction or inhibition of transporters and/or metabolic enzymes, principally cytochromes (CYPs) at the intestinal and/or hepatic levels . Furthermore, genetic polymorphism of transporters and CYPs can also modify the TKI's exposure.…”

Section: Introductionmentioning

confidence: 99%

“…Increase or decrease in the systemic exposure can result from induction or inhibition of transporters and/or metabolic enzymes, principally cytochromes (CYPs) at the intestinal and/or hepatic levels. [6][7][8] Furthermore, genetic polymorphism of transporters and CYPs can also modify the TKI's exposure. These DDIs may decrease the efficiency of treatments and/or increase adverse reactions, which can alter adherence in patients.…”

mentioning

confidence: 99%

“…Most TKIs are weak bases that have a pH-dependent solubility. 15 This decreases their solubility in the gastrointestinal tract at the site of absorption in the jejunum (pH around [5][6] or in the ileum (pH around [7][8]. Moreover, their poor solubility results also from a rather high lipophilicity, with the exception of ruxolitinib.…”

mentioning

confidence: 99%

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Pharmacokinetic drug-drug interactions of tyrosine kinase inhibitors: A focus on cytochrome P450, transporters, and acid suppression therapy

Toulet

Corre

2016

Hematological Oncology

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The extensive use of tyrosine kinase inhibitors (TKI's) in hematology and oncology has shown that these drugs have a significant potential for drug-drug interactions. Since these drugs have a rather low therapeutic window, some drug interactions are of particular clinical relevance either on drug toxicity or on patient's response. Significant interactions occur with concomitant use of acid-suppressive therapy leading to a decreased oral bioavailability. However, such interactions are drug dependent according to their solubility pattern and to the duration of action of acid-suppressive therapy, which is coprescribed. Significant interactions occur by inhibition or induction of CYP450 3A4 which is the main metabolic pathway of TKIs. However, minor metabolic pathways should also be paid attention to. Interactions involving efflux and influx transporters should also be considered occurring for some TKIs. Genetic polymorphism in drug metabolism as well as in drug transport is a factor of variability in drug exposure, which could modulate the magnitude of drug-drug interactions (DDIs). It should be noticed that TKIs can also be at the origin of drug interactions by altering the pharmacokinetics of coprescribed drugs. Since cancer patients are given many drugs either for supportive care or for the treatment of drug toxicity, and to the fact that the oldest patients are polymedicated, a clear understanding of DDIs with TKIs is of interest. The objectives of this review are to provide an overview of the mechanisms of DDIs with TKIs and to provide to physicians and pharmacists recommendations to manage these DDIs in their clinical practice.

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Section: Discussionmentioning

confidence: 99%

Section: Polymorphismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetic drug-drug interactions of tyrosine kinase inhibitors: A focus on cytochrome P450, transporters, and acid suppression therapy

Toulet

Corre

2016

Hematological Oncology

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TKI combination therapy: strategy to enhance dasatinib uptake by inhibiting Pgp‐ and BCRP‐mediated efflux

D’Cunha

Bae

Murry

et al. 2016

Biopharm & Drug Disp

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The overexpression of efflux transporters, especially P-glycoprotein (Pgp, MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2), represents an important mechanism of multidrug resistance (MDR). Tyrosine kinase inhibitors (TKIs), a novel group of target-specific anticancer drugs, have recently been found to interact with Pgp and BCRP and to serve as both substrates and inhibitors. Considering their dual role, we anticipate that combination TKI therapy may represent a promising strategy to reverse efflux transporter mediated TKI resistance. Presently, investigations on these interactions are very limited. To fill the literature gap, dasatinib was used as the model drug and the effects of various TKIs on Pgp- and BCRP- mediated dasatinib efflux were evaluated. Cell uptake studies were performed using LLC-PK1 and MDCK-II cells along with their subclones that were transfected with human Pgp and BCRP, respectively. Among the 14 TKIs screened, nine TKIs greatly inhibited Pgp-mediated dasatinib efflux at 50 μm. Further concentration dependent studies showed that imatinib, nilotinib and pazopanib were potent Pgp inhibitors with IC values of 2.42, 6.11 and 8.06 μm, respectively. Additionally, 50 μm of five TKIs greatly increased dasatinib accumulation through BCRP inhibition. Concentration dependent studies revealed that imatinib, erlotinib, nilotinib, axitinib and pazopanib were potent BCRP inhibitors with IC values of 0.94, 2.23, 2.50, 6.89 and 10.4 μm, respectively. Our findings point to potential combinations of TKIs that could enhance intracellular concentrations of the targeted TKI, overcome MDR and improve TKI efficacy. Further in vivo studies are warranted to confirm the efflux transporter-mediated TKI-TKI interaction. Copyright © 2016 John Wiley & Sons, Ltd.

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Ingredients in Fruit Juices Interact with Dasatinib Through Inhibition of BCRP: A New Mechanism of Beverage-Drug Interaction

Fleisher

Unum

Shao

et al. 2015

Journal of Pharmaceutical Sciences

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Enzyme-Transporter-Mediated Drug Interactions with Small Molecule Tyrosine Kinase Inhibitors

Cited by 37 publications

References 224 publications

Pharmacokinetic drug-drug interactions of tyrosine kinase inhibitors: A focus on cytochrome P450, transporters, and acid suppression therapy

Pharmacokinetic drug-drug interactions of tyrosine kinase inhibitors: A focus on cytochrome P450, transporters, and acid suppression therapy

TKI combination therapy: strategy to enhance dasatinib uptake by inhibiting Pgp‐ and BCRP‐mediated efflux

Ingredients in Fruit Juices Interact with Dasatinib Through Inhibition of BCRP: A New Mechanism of Beverage-Drug Interaction

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