Atypical kinetics of cytochrome P450 enzymes in pharmacology and toxicology

Leow, Jacqueline Wen Hui; Tang, Lloyd Wei Tat; Chan, Eric Chun Yong

doi:10.1016/bs.apha.2022.05.003

Cited by 5 publications

(6 citation statements)

References 123 publications

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“…This strategy falls on the premise of the well-established impact of substrate-dependency in affecting MBI potencies which could range widely even from the presence to absence of MBI with different probe substrates utilized in vitro for the same inactivator. 65 However, definitive guidance surrounding the choice of suitable representative probe substrates for the accurate characterization of auto-inactivation processes remains unavailable. MBI parameters of dronedarone and NDBD against CYP3A4 using rivaroxaban as a probe substrate were minimally adjusted to reduce inactivation potencies compared with the significant optimization to increase MBI potency of NDBD against MAO-A using kynuramine as a probe substrate as experimentally derived K I of 186 μM was clearly nonphysiological.…”

Section: Discussionmentioning

confidence: 99%

“…Reasonable recapitulation of both dronedarone and NDBD PK upon chronic oral administration of dronedarone was achieved following the iterative adjustments of autoinactivation parameters of NDBD against MAO‐A and both dronedarone and NDBD against CYP3A4. This strategy falls on the premise of the well‐established impact of substrate‐dependency in affecting MBI potencies which could range widely even from the presence to absence of MBI with different probe substrates utilized in vitro for the same inactivator 65 . However, definitive guidance surrounding the choice of suitable representative probe substrates for the accurate characterization of auto‐inactivation processes remains unavailable.…”

Section: Discussionmentioning

confidence: 99%

“…tural differences between kynuramine (molecular weight [MW]: 164.2) and NDBD (MW: 500.7) exist especially pertaining to molecular size compared with rivaroxaban (MW: 435.9) and NDBD. Multiple binding sites within the active site of an enzyme have been proposed to promote simultaneous covalent adduction of reactive metabolites, that is, MBI alongside productive binding of an alternative substrate,65 which could explain the high K I of NDBD MBI against MAO-A metabolism of kynuramine. Despite the discussed model limitations, accurate recapitulation of dronedarone and NDBD PK following clinically relevant doses of 400 mg dronedarone across single (Table3) and multiple oral dosing studies (Figure2C,D and Table 4)reinforcesconfidence in the reliability of our model for the quantitative simulation of PK parameters of dronedarone and NDBD in clinically observed scenarios.…”

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

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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“…While kinetic constants such as K i were classically regarded as intrinsic features of the inhibitor and were thought to be independent of the surrogate probe substrate utilized, there is now a growing consensus in the field that such reductionistic assumptions are only valid when both the probe substrate and inhibitor are competing for access to the same binding site on the P450 enzyme . It has been consistently demonstrated that K i values can vary drastically depending on the choice of probe substrate that is employed in the assay. ,− This invariably leads to a quandary because the K i values of a particular perpetrator drug obtained using the FDA-recommended probes may not be representative of another victim drug, therefore casting doubt on the reliability of DDI predictions gleaned from conventional experimental approaches.…”

Section: Introductionmentioning

confidence: 99%

Probe Substrate Dependencies in CYP3A4 Allosteric Inhibition: A Novel Molecular Mechanism Involving F–F′ Loop Perturbations

Wei,

Tang,

Verma

et al. 2024

J. Chem. Inf. Model.

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The biochemical basis for substrate dependences in apparent inhibition constant values (K i ) remains unknown. Our study aims to elucidate plausible structural determinants underpinning these observations. In vitro steady-state inhibition assays conducted using human recombinant CYP3A4 enzyme and testosterone substrate revealed that fibroblast growth factor receptor (FGFR) inhibitors erdafitinib and pemigatinib noncompetitively inhibited CYP3A4 with apparent K i values of 10.2 ± 1.1 and 3.3 ± 0.9 μM, respectively. However, when rivaroxaban was adopted as the probe substrate, there were 2.0-and 3.2-fold decreases in its apparent K i values. To glean mechanistic insights into this phenomenon, erdafitinib and pemigatinib were docked to allosteric sites in CYP3A4. Subsequently, molecular dynamics (MD) simulations of apo-and holo-CYP3A4 were conducted to investigate the structural changes induced. Comparative structural analyses of representative MD frames extracted by hierarchical clustering revealed that the allosteric inhibition of CYP3A4 by erdafitinib and pemigatinib did not substantially modulate its active site characteristics. In contrast, we discovered that allosteric binding of the FGFR inhibitors reduces the structural flexibility of the F−F′ loop region, an important gating mechanism to regulate access of the substrate to the catalytic heme. We surmised that the increased rigidity of the F-F′ loop engenders a more constrained entrance to the CYP3A4 active site, which in turn impedes access to the larger rivaroxaban molecule to a greater extent than testosterone and culminates in more potent inhibition of its CYP3A4-mediated metabolism. Our findings suggest a potential mechanism to rationalize probe substrate dependencies in K i arising from the allosteric noncompetitive inhibition of CYP3A4.

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“…By contrast, the CYP kinetic profiles are rather complicated, depending on the CYP isoforms, catalyzed substrates, and additives such as the effectors. They can be divided into four categories according to the graphical representations: biphasic kinetics, sigmoidal kinetics, partial inhibition, and complete inhibition . While there is no consensus on the underlying cause of the phenomenon, multiple hypotheses have been proposed to provide explanations.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Ligand-Binding Sites of CYP3A4 by Molecular Dynamics Simulations with Solvent Probes

Feng,

Gong,

Zhu

et al. 2024

J. Chem. Inf. Model.

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Cytochrome P450 3A4 (CYP3A4) is one of the most important drug-metabolizing enzymes in the human body and is well known for its complicated, atypical kinetic characteristics. The existence of multiple ligand-binding sites in CYP3A4 has been widely recognized as being capable of interfering with the active pocket through allosteric effects. The identification of ligand-binding sites other than the canonical active site above the heme is especially important for understanding the atypical kinetic characteristics of CYP3A4 and the intriguing association between the ligand and the receptor. In this study, we first employed mixed-solvent molecular dynamics (MixMD) simulations coupled with the online computational predictive tools to explore potential ligand-binding sites in CYP3A4. The MixMD approach demonstrates better performance in dealing with the receptor flexibility compared with other computational tools. From the sites identified by MixMD, we then picked out multiple sites for further exploration using ensemble docking and conventional molecular dynamics (cMD) simulations. Our results indicate that three extra sites are suitable for ligand binding in CYP3A4, including one experimentally confirmed site and two novel sites.

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Atypical kinetics of cytochrome P450 enzymes in pharmacology and toxicology

Cited by 5 publications

References 123 publications

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

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

Probe Substrate Dependencies in CYP3A4 Allosteric Inhibition: A Novel Molecular Mechanism Involving F–F′ Loop Perturbations

Unraveling the Ligand-Binding Sites of CYP3A4 by Molecular Dynamics Simulations with Solvent Probes

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