Assessment of the Time‐Dependent Inhibition (TDI) Potential of Test Compounds with Human Liver Microsomes by IC<sub>50</sub> Shift Method Using a Nondilution Approach

Ron, Lian de; Rajaraman, Ganesh

doi:10.1002/0471141755.ph0714s58

Cited by 3 publications

(3 citation statements)

References 6 publications

(7 reference statements)

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“…Therefore, the result of in vitro CYP reaction phenotyping, CYP inhibition, CYP induction, and transporter assays are useful and insightful to assess the DDI potential of tested drugs in vivo. 16,17 The objective of this study was to evaluate the DDI potential of our newly developed anticancer drug-polymer conjugate, fb-PMT, using both in silico and in vitro approaches. We initially used the ADMET Predictor software to predict potential CYP metabolites of fb-PMT and the potential to inhibit various CYP isoforms.…”

Section: How Might This Change Clinical Pharmacology or Translational...mentioning

confidence: 99%

“…These assays are typically carried out in transfected cell lines expressing the transporter of interest, or in Caco‐2 cell lines. Therefore, the result of in vitro CYP reaction phenotyping, CYP inhibition, CYP induction, and transporter assays are useful and insightful to assess the DDI potential of tested drugs in vivo 16,17 …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Preclinical assessment of drug–drug interaction of fb‐PMT, a novel anti‐cancer thyrointegrin αvβ3 antagonist

Fujioka

Fekry

Rumsey

et al. 2023

Clinical Translational Sci

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The objective of the current study was to identify potential drug–drug interactions (DDIs) with the drug candidate fb‐PMT, a novel anticancer thyrointegrin αvß3 antagonist. This was accomplished by using several in vitro assays to study interactions of fb‐PMT with both cytochrome P450 (CYP) enzymes and drug transporters, two common mechanisms leading to adverse drug effects. In vitro experiments showed that fb‐PMT exhibited weak reversible inhibition of CYP2C19 and CYP3A4. In addition, fb‐PMT did not show time‐dependent inhibition with any of the seven CYP isoforms tested, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4. Human liver microsomal incubations demonstrated that fb‐PMT is stable. Potential transporter‐mediated DDIs with fb‐PMT were assessed with two ATP binding cassette (ABC) family transporters (P‐glycoprotein and breast cancer resistance protein) using Caco2 cells and seven solute carrier family (SLC) transporters (organic cation transporter OCT2, organic anion transporters OAT1 and OAT3, organic anion transporter peptides OATP1B1 and OATP1B3, and the multidrug and toxic extrusion proteins MATE1 and MATE2‐K using transfected HEK293 cells). Fb‐PMT was not a substrate for any of the nine transporters tested in this study, nor did it inhibit the activity of seven of the transporters tested. However, fb‐PMT inhibited the uptake of rosuvastatin by both OATP1B1 and OATP1B3 with half‐maximal inhibitory concentrations greater than 3 and less than 10 μM. In summary, data suggest that the systemic administration of fb‐PMT is unlikely to lead to DDIs through CYP enzymes or ABC and SLC transporters in humans.

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Section: How Might This Change Clinical Pharmacology or Translational...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Preclinical assessment of drug–drug interaction of fb‐PMT, a novel anti‐cancer thyrointegrin αvβ3 antagonist

Fujioka

Fekry

Rumsey

et al. 2023

Clinical Translational Sci

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In Vitro Inhibitory Effects of Agarwood Tea (Aquilaria malaccensis Lamk) Aqueous Extract on Human Cytochrome P450 (CYP) Enzyme Activities

Pan

Tze

Jagadish

et al. 2022

DMBL

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Background: Agarwood tea derived from Aquilaria malaccensis Lamk, is becoming an increasingly popular herbal drink that has said to have multiple health benefits. Co-administration of this tea and clinical used drugs are possible, and hence increasing risk of drug-herb interactions. Objectives: This in vitro study investigated the inhibitory effects of agarwood tea aqueous extract on the eight major human drug-metabolising cytochrome P450 (CYP) enzyme activities. Methods: High-throughput fluorescence-based Vivid® CYP450 screening kits were employed to obtain the enzyme activities before and after incubation with agarwood tea aqueous extract. Results: Agarwood aqueous extract potently inhibited CYP2C9, CYP2D6, and CYP3A4 activities with Ki values of 5.1, 34.5, and 20.3µg/ml, respectively. The most likely inhibition mode responsible for these inhibitions was non-competitive inhibition. On the other hand, at 1000µg/ml, agarwood tea aqueous extract negligibly inhibited CYP1A2, CYP2B6, CYP2C19, CYP2E1, and CYP3A5 activities. Conclusion: These findings can be used to design additional in vitro investigations using clinical relevant drug substrates for CYP2C9, CYP2D6, and CYP3A4. Subsequently, future studies can be conducted to determine potential interactions between agarwood tea aqueous extract and CYP using in vivo models.

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Modulatory Effects of Mangiferin Isolated from Aquilaria Plants on Human Cytochrome P450 Enzyme (CYP) Activities In vitro and In silico Studies

Pan

Jagadiah

Ung

et al. 2023

NPJ

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Background: Mangiferin has been identified as one of the major active constituents of Aquilaria plants. It was reported to have several promising chemotherapeutic potentials. Our preliminary data suggested that Aquilaria plant water extracts inhibited several cytochrome P450 (CYP) isoenzymes in vitro. Objective: This study aimed to investigate the modulatory effects of mangiferin on six major drug metabolizing CYP enzymes including CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP3A4, and CYP3A5. Methods: The enzyme activities were measured using fluorescence-based assays and enzyme kinetic such as IC50 parameters and Ki values were calculated to evaluate inhibitory potencies and mechanisms. Moreover, for potent inhibitions, molecular docking studies were carried out to explore potential interactions of residues between mangiferin and CYP enzymes. Results: Our findings suggested that mangiferin could inhibit CYP2D6, CYP3A4, and CYP3A5 in vitro with IC50 values of 9.2, 8.7, and 4.3µM, and Ki values of 3.8, 10.8, and 9.6µM, in a non-competitive inhibition pattern. Molecular docking studies using AutoDock 4.2 identified potential residues contained in mangiferin that interacted with CYP2D6, CYP3A4, and CYP3A5, resulting in the observed inhibitory effects. Conclusion: Mangiferin should be used carefully, in particular, with conventional drugs metabolized mainly by CYP2D6, CYP3A4, and CYP3A5. Further in vivo studies are recommended to evaluate the clinical relevance of these inhibitions.

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Assessment of the Time‐Dependent Inhibition (TDI) Potential of Test Compounds with Human Liver Microsomes by IC₅₀ Shift Method Using a Nondilution Approach

Cited by 3 publications

References 6 publications

Preclinical assessment of drug–drug interaction of fb‐PMT, a novel anti‐cancer thyrointegrin αvβ3 antagonist

Preclinical assessment of drug–drug interaction of fb‐PMT, a novel anti‐cancer thyrointegrin αvβ3 antagonist

In Vitro Inhibitory Effects of Agarwood Tea (Aquilaria malaccensis Lamk) Aqueous Extract on Human Cytochrome P450 (CYP) Enzyme Activities

Modulatory Effects of Mangiferin Isolated from Aquilaria Plants on Human Cytochrome P450 Enzyme (CYP) Activities In vitro and In silico Studies

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Assessment of the Time‐Dependent Inhibition (TDI) Potential of Test Compounds with Human Liver Microsomes by IC50 Shift Method Using a Nondilution Approach

Cited by 3 publications

References 6 publications

Preclinical assessment of drug–drug interaction of fb‐PMT, a novel anti‐cancer thyrointegrin αvβ3 antagonist

Preclinical assessment of drug–drug interaction of fb‐PMT, a novel anti‐cancer thyrointegrin αvβ3 antagonist

In Vitro Inhibitory Effects of Agarwood Tea (Aquilaria malaccensis Lamk) Aqueous Extract on Human Cytochrome P450 (CYP) Enzyme Activities

Modulatory Effects of Mangiferin Isolated from Aquilaria Plants on Human Cytochrome P450 Enzyme (CYP) Activities In vitro and In silico Studies

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Product

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Assessment of the Time‐Dependent Inhibition (TDI) Potential of Test Compounds with Human Liver Microsomes by IC₅₀ Shift Method Using a Nondilution Approach