Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts

Karkhanis, Aneesh; Venkatesan, Gopalakrishnan; Kambayashi, Ryuichi; Leow, Jacqueline Wen Hui; Han, Marcus Qingrui; Izumi-Nakaseko, Hiroko; Goto, Ai; Soh, Boon Seng; Kojodjojo, Pipin; Sugiyama, Atsushi; Chan, Eric Chun Yong

doi:10.1016/j.apsb.2022.03.008

Cited by 13 publications

(12 citation statements)

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“…Subsequently, we demonstrated that dronedarone caused mitochondrial injury in rat cardiomyocytes which was mitigated via exogenous 11,12-EET and 14,15-EET enrichment (Karkhanis et al, 2018). Recently, we demonstrated that dronedarone treatment or CYP2J2 knockdown in human cardiomyocytes resulted in proarrhythmia (Karkhanis et al, 2022). Our collective findings provided compelling evidences that the dysregulation of CYP2J2-mediated AA-EETs metabolism affects both the viability and normal beating function of cardiomyocytes.…”

Section: Discussionmentioning

confidence: 61%

Inhibition of Cytochrome P450 2J2-Mediated Metabolism of Rivaroxaban and Arachidonic Acid by Ibrutinib and Osimertinib

Wang

Chan

2022

Drug Metab Dispos

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Covalent tyrosine kinase inhibitors (TKIs) ibrutinib and osimertinib are associated with cardiac arrhythmia. The interactions between these TKIs with cytochrome P450 2J2 (CYP2J2) that is highly expressed in human heart are unknown. In vitro metabolism experiments were performed to characterize CYP2J2-mediated metabolism of ibrutinib and osimertinib. Unbound distribution coefficient (K puu ) for both TKIs was determined in AC16 cardiomyocytes. In vitro reversible and time-dependent CYP2J2 inhibition experiments were conducted with exogenous and endogenous substrates, namely rivaroxaban and arachidonic acid (AA), respectively, where kinetic parameters were estimated via one-site and multisite kinetic modeling. Ibrutinib was efficiently metabolized by CYP2J2 to a hydroxylated metabolite, M35, following substrate inhibition kinetics. Osimertinib is not a substrate of CYP2J2. Both TKIs depicted K puu values above 1 and equipotently inhibited CYP2J2-mediated hydroxylation of rivaroxaban in a concentration-dependent manner without time-dependency. The mode of reversible inhibition of CYP2J2-mediated metabolism of rivaroxaban and AA by osimertinib was described by Michaelis-Menten kinetics, while a two-site kinetic model recapitulated the atypical inhibitory kinetics of ibrutinib assuming multiple substratebinding domains within the CYP2J2 active site. The inhibition of ibrutinib and osimertinib on cardiac AA metabolism could be clinically significant considering the preferable distribution of both TKIs to cardiomyocytes with R cut-off values of 1.160 and 1.026, respectively. The dysregulation of CYP2J2-mediated metabolism of AA to cardioprotective epoxyeicosatrienoic acids by ibrutinib and osimertinib serves as a novel mechanism for TKI-induced cardiac arrhythmia. Mechanistic characterization of This article has not been copyedited and formatted. The final version may differ from this version.

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Section: Discussionmentioning

confidence: 61%

Inhibition of Cytochrome P450 2J2-Mediated Metabolism of Rivaroxaban and Arachidonic Acid by Ibrutinib and Osimertinib

Wang

Chan

2022

Drug Metab Dispos

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“…Using known enzyme concentrations and batch-specific protein concentrations for recombinant enzymes used in various in vitro assays (including metabolism, RI and MBI) as well as physicochemical properties of the compound investigated, the fraction unbound in microsomal fraction (f u,mic ) for respective experimental parameters was calculated using Simcyp Prediction Toolbox. To provide an estimate for the auto-inhibition/inactivation effect on metabolizing enzymes of dronedarone and NDBD, in vitro RI 15 and MBI 16 parameters of dronedarone against CYP3A4/5 and CYP2J2…”

Section: Hepatic Metabolism Of Dronedarone and Ndbdmentioning

confidence: 99%

“…For the prospective DDI simulation between dronedarone/NDBD as the perpetrator drug and rivaroxaban as the victim drug, a previously established and verified PBPK model of rivaroxaban was utilized for the construction of the PBPK-DDI model. 29 MBI and/or RI parameters of dronedarone 15,16 and/or NDBD against CYP3A4/5-and CYP2J2mediated metabolism of rivaroxaban as well as OAT3- 32 and P-gpmediated transport of rivaroxaban 15 were incorporated into the model appropriately (Table S3). Chronic dosing regimens of dronedarone revealed that in vivo steady-state concentrations were achieved in approximately 3-4 days for dronedarone and 4-5 days for NDBD.…”

Section: Model Application: Prospective Ddi Simulation With Rivaroxab...mentioning

confidence: 99%

“…13 The mechanism could probably be attributed to the auto-inactivation of CYP3A since both dronedarone and NDBD exhibit reversible inhibition (RI) and mechanism-based inactivation (MBI) against CYP3A4 as reported by our laboratory. 15,16 To accurately determine the impact of auto-inactivation of key hepatic metabolizing enzymes in contributing to nonlinear PK, an understanding of the hepatic concentrations of dronedarone and NDBD becomes pertinent. As amiodarone has been recognized as a substrate of organic anion-transporting polypeptide (OATP) 2B1, 17 it is plausible that OATP transporters may be implicated in hepatic uptake kinetics of dronedarone and NDBD, which need to be characterized.…”

Section: Introductionmentioning

confidence: 99%

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Development and verification of a physiologically based pharmacokinetic model of dronedarone and its active metabolite N‐desbutyldronedarone: Application to prospective simulation of complex drug–drug interaction with rivaroxaban

Leow

Ang

Chan

2023

Brit J Clinical Pharma

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Aims Despite potential enzyme‐ and transporter‐mediated drug–drug interactions (DDIs) between dronedarone and rivaroxaban in atrial fibrillation (AF) patients, pharmacokinetic/pharmacodynamic data remain limited to guide clinical practice. We aimed to develop, verify and validate a physiologically based pharmacokinetic (PBPK) model of dronedarone and its major metabolite, N‐desbutyldronedarone (NDBD), to prospectively interrogate this clinically relevant DDI in healthy and mild renal impairment populations. Methods The middle‐out development of our PBPK model combined literature‐derived or in‐house in vitro data, predicted in silico data and in vivo clinical data. Model verification was performed for intravenous and oral (single and multiple) dosing regimens. Model validation for the accurate prediction of cytochrome P450 (CYP)3A4‐ and P‐glycoprotein‐mediated DDI utilized simvastatin and digoxin as respective victim drugs. Rivaroxaban‐specific inhibitory parameters of dronedarone and/or NDBD against CYP3A4, CYP2J2, OAT3 and P‐glycoprotein were incorporated into the PBPK‐DDI model for prospective dronedarone–rivaroxaban DDI simulation. Results Dronedarone and NDBD PK following clinically relevant doses of 400 mg dronedarone across single and multiple oral dosing were accurately simulated by incorporating effect of auto‐inactivation on dose nonlinearities. Following successful model validation, nondose‐adjusted rivaroxaban–dronedarone DDI in healthy and mild renal impairment populations revealed simulated rivaroxaban area under the plasma concentration–time curve up to 24 h fold change greater than dose exposure equivalence (0.70–1.43) at 1.65 and 1.84, respectively. Correspondingly, respective major bleeding risk was 4.24 and 4.70% compared with threshold of 4.5% representing contraindicated rivaroxaban–ketoconazole DDI. Conclusion Our PBPK‐DDI model predicted clinically significant dronedarone–rivaroxaban DDI in both healthy and mild renal impairment subjects. Greater benefit vs. risk could be achieved with rivaroxaban dose reductions to at least 15 mg in mild renal impairment subjects on concomitant dronedarone and rivaroxaban.

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“…[20][21][22][23] For example, deuterated active pharmaceutical ingredients (d-APIs) in some cases can retard or alter API metabolism in vivo due the primary kinetic isotope effect of CH bonds, which can extend the lifetime of therapeutics and allow for a lower dosing than the conventional APIs to achieve the same pharmacological activity. [24][25][26] Although there is considerable clinical activity currently 4 surrounding the d-APIs, some have even been recognized by the Food and Drug Administration.…”

Section: Introductionmentioning

confidence: 99%

Deuteron-proton isotope correlation spectroscopy of molecular solids

Welton

Trébosc²,

Jain

et al. 2022

Preprint

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A dissolution followed by recrystallization from a deuterated solvent allows the site-selective deuteration of labile protons in molecular solids. High yields of deuteration obtained by this approach facilitates the structure elucidation of powdered solids by solid-state NMR spectroscopy, for example, by acquiring 1D 2H and 2D 2H-1H correlation NMR spectra with short experimental times. Along these lines, we present a cross-polarization 2H-1H isotope correlation spectroscopy (CP-iCOSY) approach for the characterization of deuterated amino acids and pharmaceutical compounds. We show that the high field NMR (28.2 T) coupled with fast magic-angle spinning (MAS) overcomes the sensitivity and resolution barrier for acquiring 2H MAS spectra, enabling the rapid detection of 2H peaks in a few seconds to minutes. Specifically, two-dimensional 2H-1H CP-iCOSY experiment allows the local structures and through-space interactions in a partially deuterated compounds to be elucidated. Analysis of partially deuterated L-histidine·HCl·H2O and dopamine.HCl is presented, whereby the detection of 2D peaks corresponding to 2H-1H pairs separated by >4 Å demonstrates the sensitivity and resolution power of the presented approach for the characterization of solid-state packing interactions. 2D ssNMR results are corroborate by NMR crystallography analysis using Gauge Including Projector Augmented Wave (GIPAW) approach. Molecular-level analysis enabled by this study is of considerable interest for further investigation of labile sites in a variety of molecular solids, reactive surfaces and interfaces, and supramolecular assemblies.

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Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts

Cited by 13 publications

References 81 publications

Inhibition of Cytochrome P450 2J2-Mediated Metabolism of Rivaroxaban and Arachidonic Acid by Ibrutinib and Osimertinib

Inhibition of Cytochrome P450 2J2-Mediated Metabolism of Rivaroxaban and Arachidonic Acid by Ibrutinib and Osimertinib

Development and verification of a physiologically based pharmacokinetic model of dronedarone and its active metabolite N‐desbutyldronedarone: Application to prospective simulation of complex drug–drug interaction with rivaroxaban

Deuteron-proton isotope correlation spectroscopy of molecular solids

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