Novel Binding Mode of the Acidic CYP2D6 Substrates Pactimibe and Its Metabolite R-125528

Kotsuma, Masakatsu; Hanzawa, Hiroyuki; Iwata, Yoriko; Takahashi, Kenji; Tokui, Taro

doi:10.1124/dmd.108.020776

Cited by 12 publications

(9 citation statements)

References 34 publications

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“…N-Dealkyl metoprolol acid showed similar affinity to quinidine, a model for CYP2D6 inhibitor, in binding to the catalytic site on CYP2D6, but it did not interact with either Asp301 or Glu216, which generally interacted with typical CYP2D6 substrates (Kotsuma et al, 2009). Phe120, a key amino acid residue, was very important in the terms of selection and region specification of substrates binding to CYP2D6.…”

Section: Discussionmentioning

confidence: 96%

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug–drug and drug–herb interaction by LC‐ESI/MS/MS

Borkar

Bhandi

Dubey

et al. 2016

Biomedical Chromatography

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The aim of the present study was to evaluate the contribution of metabolites to drug-drug interaction and drug-herb interaction using the inhibition of CYP2D6 and CYP3A4 by metoprolol (MET) and its metabolites. The peak concentrations of unbound plasma concentration of MET, α-hydroxy metoprolol (HM), O-desmethyl metoprolol (ODM) and N-desisopropyl metoprolol (DIM) were 90.37 ± 2.69, 33.32 ± 1.92, 16.93 ± 1.70 and 7.96 ± 0.94 ng/mL, respectively. The metabolites identified, HM and ODM, had a ratio of metabolic area under the concentration-time curve (AUC) to parent AUC of ≥0.25 when either total or unbound concentration of metabolite was considered. In vitro CYP2D6 and CYP3A4 inhibition by MET, HM and ODM study revealed that MET, HM and ODM were not inhibitors of CYP3A4-catalyzed midazolam metabolism and CYP2D6-catalyzed dextromethorphan metabolism. However, DIM only met the criteria of >10% of the total drug related material and <25% of the parent using unbound concentrations. If CYP inhibition testing is solely based on metabolite exposure, DIM metabolite would probably not be considered. However, the present study has demonstrated that DIM contributes significantly to in vitro drug-drug interaction. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 96%

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug–drug and drug–herb interaction by LC‐ESI/MS/MS

Borkar

Bhandi

Dubey

et al. 2016

Biomedical Chromatography

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“…4), which is consistent with previous studies. [30][31][32][33][34][35][36][37] Analyses of representative protein structures sampled from the trajectory of MD simulations: Investigating representative structures from the trajectory of the MD simulation allowed us to identify differences in the protein structures of CYP2D6.1 and CYP2D6.17 and helped elucidate differences in their drug interactions. There were major structural differences between CYP2D6.1 and CYP2D6.17.…”

Section: Discussionmentioning

confidence: 99%

“…Phe120 and Phe483 have been suggested to mediate hydrophobic interactions, such as ³-³ interactions, and Glu216, Asp301, and Ser304 to mediate hydrogen bonding with ligands, from the results of docking studies and site-directed mutagenesis experiments. [30][31][32][33][34][35][36][37][38] However, these earlier docking experiments used an apoprotein CYP2D6.1 structure [PDB (Protein Data Bank) code 2F9Q]. 39) Recently, the X-ray structure for CYP2D6.1 co-crystallized with prinomastat (PDB code 3QM4) has been resolved, which clearly showed that a large conformational change in CYP2D6 resulted from ligand binding and which identified the novel F' helix.…”

Section: Introductionmentioning

confidence: 99%

In Silieo Study on the Inhibitory Interaction of Drugs with Wild-type CYP2D6.1 and the Natural Variant CYP2D6.17

Handa

Izumi

Yamaotsu

et al. 2014

Drug Metabolism and Pharmacokinetics

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The natural variant of the cytochrome P450 enzyme CYP2D6.1, CYP2D6.17, is most common in African populations, has three amino acid substitutions (T107I, R296C, and S486T) compared to the wild-type, and is known to have a different ligand preference from CYP2D6.1. It is becoming increasingly important to understand differences in the metabolism of medicines in different ethnic groups in order to assess the relevance of clinical data from different countries. This study investigated differences in the inhibition profiles of drugs for CYP2D6 with respect to gene polymorphisms. Firstly, we used computer docking with six drugs to several CYP2D6.1 structures, sampled from the trajectory of MD simulations, and calculated MM-GB/SA scores representing binding free energies. We then used regression analysis to predict the potency with which drugs inhibited CYP2D6.1 based on MM-GB/SA scores. The pKi-values obtained were in good agreement with experimental values measured for the six drugs (r(2) = 0.81). We carried out the same analysis for CYP2D6.17 and the pKi-values calculated were also in good agreement with experimental values (r(2) = 0.92). Finally, we were able to successfully explain the different abilities of CYP2D6.1 and CYP2D6.17 to metabolize drugs in different ethnic groups with reference to their 3D-structures.

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“…When the terpene moiety in CBD is located close to the heme, the pentyl side chain in the cannabinoid is thought to be fixed within the proposed hydrophobic region corresponding to a toe area of the foot-shaped cavity in CYP2D6 (Rowland et al, 2006). On the other hand, when the pentyl side chain of CBD is positioned near the heme, the 4Љ-or 5Љ-position of the side chain is located above the heme, and the proximal portion of the side chain is considered to interact with the proposed hydrophobic region defined by hydrophobic residues, such as a Met residue at site 374 and Leu residues at sites 213 and 484 (de Graaf et al, 2007;Kotsuma et al, 2008). In both cases, the side-chain shortening of CBD may lead to unstable binding of the cannabinoid within the active site in CYP2D6 because of attenuation of the hydrophobic interactions.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6

Yamaori¹,

Okamoto²,

Yamamoto³

et al. 2011

Drug Metab Dispos

135

104

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Novel Binding Mode of the Acidic CYP2D6 Substrates Pactimibe and Its Metabolite R-125528

Cited by 12 publications

References 34 publications

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug–drug and drug–herb interaction by LC‐ESI/MS/MS

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug–drug and drug–herb interaction by LC‐ESI/MS/MS

In Silieo Study on the Inhibitory Interaction of Drugs with Wild-type CYP2D6.1 and the Natural Variant CYP2D6.17

Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6

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