Novel isomeric metabolite profiles correlate with warfarin metabolism phenotype during maintenance dosing in a pilot study of 29 patients

Pouncey, Dakota L.; Hartman, Jessica H.; Moore, Page C.; Dillinger, David J.; Dickerson, Kimberly W; Sappington, Daniel R.; Smith, Eugene S.; Boysen, Gunnar; Miller, Grover P.

doi:10.1097/mbc.0000000000000752

Cited by 5 publications

(12 citation statements)

References 41 publications

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“…Major oxidative metabolic pathways for warfarin yield primarily 7- and 10-hydroxywarfarin ( Locatelli, et al, 2005 ; Pouncey, et al, 2018 ) making them more relevant to in vivo clearance pathways, and so we carried out phenotyping assays using reductase inhibitors to identify enzymes responsible for the reduction of those hydroxywarfarins ( Figures 6A,B ). The inhibition patterns for the major alcohol were similar for both substrates with about 30% inhibition by H-FFA, 60% inhibition by QUE, and 70% decrease in activity with H-INDO.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, 6-, 7-, 8- and 4′-hydroxywarfarins readily undergo glucuronidation ( Zielinska, et al, 2007 ; Bratton, et al, 2012 ; Kim, et al, 2019 ; Pugh, et al, 2018 ) to yield glucuronides excreted in the urine ( Kaminsky and Zhang 1997 ; Miller, Jones, et al, 2009 ). The effectiveness of those pathways presumably explains the very low nanomolar levels of those hydroxywarfarins in patient plasma ( Haque, et al, 2014 ; Pouncey, et al, 2018 ), including S -7-hydroxywarfarin, a metabolite of the main pathway for S -warfarin elimination ( Krishna Kumar et al, 2013 ; Rettie, et al, 1992 ). In contrast, 10-hydroxywarfarin is not detectable in patient urine ( Miller, Jones, et al, 2009 ) and accumulates collectively almost up to micromolar levels in patient plasma following warfarin maintenance dosing ( Haque, et al, 2014 ; Pouncey, et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…The effectiveness of those pathways presumably explains the very low nanomolar levels of those hydroxywarfarins in patient plasma ( Haque, et al, 2014 ; Pouncey, et al, 2018 ), including S -7-hydroxywarfarin, a metabolite of the main pathway for S -warfarin elimination ( Krishna Kumar et al, 2013 ; Rettie, et al, 1992 ). In contrast, 10-hydroxywarfarin is not detectable in patient urine ( Miller, Jones, et al, 2009 ) and accumulates collectively almost up to micromolar levels in patient plasma following warfarin maintenance dosing ( Haque, et al, 2014 ; Pouncey, et al, 2018 ). The resulting 10-hydroxywarfarin levels are sufficient to potentate anticoagulation directly by inhibiting VKORC1 ( Haque, et al, 2014 ) and indirectly by inhibiting S -warfarin metabolism ( Jones, et al, 2010c ).…”

Section: Discussionmentioning

confidence: 99%

“…As major oxidized warfarin metabolites, rac -7- and 10 hydroxywarfarin attain the highest levels in patients ( Locatelli, et al, 2005 ; Pouncey, et al, 2018 ), and thus, reductases involved in their metabolism may have clinical relevance. Consequently, we identified those enzymes using inhibitors relatively specific for common cytosolic reductases.…”

Section: Methodsmentioning

confidence: 99%

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Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin

et al. 2022

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Coumadin (R/S-warfarin) anticoagulant therapy is highly efficacious in preventing the formation of blood clots; however, significant inter-individual variations in response risks over or under dosing resulting in adverse bleeding events or ineffective therapy, respectively. Levels of pharmacologically active forms of the drug and metabolites depend on a diversity of metabolic pathways. Cytochromes P450 play a major role in oxidizing R- and S-warfarin to 6-, 7-, 8-, 10-, and 4′-hydroxywarfarin, and warfarin alcohols form through a minor metabolic pathway involving reduction at the C11 position. We hypothesized that due to structural similarities with warfarin, hydroxywarfarins undergo reduction, possibly impacting their pharmacological activity and elimination. We modeled reduction reactions and carried out experimental steady-state reactions with human liver cytosol for conversion of rac-6-, 7-, 8-, 4′-hydroxywarfarin and 10-hydroxywarfarin isomers to the corresponding alcohols. The modeling correctly predicted the more efficient reduction of 10-hydroxywarfarin over warfarin but not the order of the remaining hydroxywarfarins. Experimental studies did not indicate any clear trends in the reduction for rac-hydroxywarfarins or 10-hydroxywarfarin into alcohol 1 and 2. The collective findings indicated the location of the hydroxyl group significantly impacted reduction selectivity among the hydroxywarfarins, as well as the specificity for the resulting metabolites. Based on studies with R- and S-7-hydroxywarfarin, we predicted that all hydroxywarfarin reductions are enantioselective toward R substrates and enantiospecific for S alcohol metabolites. CBR1 and to a lesser extent AKR1C3 reductases are responsible for those reactions. Due to the inefficiency of reactions, only reduction of 10-hydroxywarfarin is likely to be important in clearance of the metabolite. This pathway for 10-hydroxywarfarin may have clinical relevance as well given its anticoagulant activity and capacity to inhibit S-warfarin metabolism.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin

et al. 2022

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“…Following the oral administration of warfarin enantiomers, both R-and S-warfarin are absorbed rapidly and eliminated primarily through cytochrome P450 (CYP) mediated hepatic metabolism, to form multiple monohydroxylated metabolites (Kaminsky and Zhang, 1997;Ufer, 2005). Swarfarin, the pharmacologically more active enantiomer of warfarin, is primarily (>80%) metabolized by CYP2C9 to form either 7-or 6-hydroxy (OH)-S-warfarin, although 4'-, 8-and 10-OH-S-warfarin can also be formed via catalysis by other CYPs such as CYP2C19 and CYP3A4 (Rettie et al, 1992;Ufer, 2005;Pouncey et al, 2018). R-warfarin, in contrast, is metabolized by multiple CYP enzymes, such as CYP1A2, CYP2C19 and CYP3A4, to form 4'-, 6-, 7-, 8-and 10-OH-R-warfarin (Zhang et al, 1995;Wienkers et al, 1996;Ufer, 2005;Rettie and Tai, 2006;Pouncey et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Modeling of Warfarin ІI – Model-Based Analysis of Warfarin Metabolites after Warfarin Administered Either Alone or Together with Fluconazole or Rifampin

et al. 2022

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The objective of this study is to conduct a population pharmacokinetic (PK) model-based analysis on 10 warfarin metabolites (4'-, 6-, 7-, 8-and 10-hydroxylated (OH)-S-and Rwarfarin), when warfarin is administered alone or together with either fluconazole or rifampin.One or two compartment PK models expanded from target mediated drug disposition (TMDD) models developed previously for warfarin enantiomers were able to sufficiently characterize the PK profiles of 10 warfarin metabolites in plasma and urine under different conditions. Modelbased analysis shows CYP2C9 mediated metabolic elimination pathways are more inhibitable by fluconazole (% formation CL (CL f ) of 6-and 7-OH-S-warfarin decrease: 73.2% and 74.8%) but less inducible by rifampin (% CL f of 6-and 7-OH-S-warfarin increase: 85% and 75%), compared with non-CYP2C9 mediated elimination pathways (% CL f of 10-OH-S-warfarin and CL R of S-warfarin decrease in the presence of fluconazole: 65.0% and 15.3%; % CL f of 4'-8and 10-OH-S-warfarin increase in the presence of rifampin: 260%, 127% and 355%), which potentially explains the CYP2C9 genotype-dependent DDIs exhibited by S-warfarin, when warfarin is administrated together with fluconazole or rifampin. Additionally, for subjects with CYP2C9 *2 and *3 variants, a model-based analysis of warfarin metabolite profiles in subjects with various CYP2C9 genotypes demonstrates CYP2C9 mediated elimination is less important and non-CYP2C9 mediated elimination is more important, compared with subjects without these variants. To our knowledge, this is so far one of the most comprehensive population-based PK analyses of warfarin metabolites in subjects with various CYP2C9 genotypes under different comedications.

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A physiologically‐based pharmacokinetic/pharmacodynamic modeling approach for drug–drug‐gene interaction evaluation of S‐warfarin with fluconazole

Geng,

Shen,

Wang

et al. 2024

CPT Pharmacom & Syst Pharma

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Warfarin is a widely used anticoagulant, and its S‐enantiomer has higher potency compared to the R‐enantiomer. S‐warfarin is mainly metabolized by cytochrome P450 (CYP) 2C9, and its pharmacological target is vitamin K epoxide reductase complex subunit 1 (VKORC1). Both CYP2C9 and VKORC1 have genetic polymorphisms, leading to large variations in the pharmacokinetics (PKs) and pharmacodynamics (PDs) of warfarin in the population. This makes dosage management of warfarin difficult, especially in the case of drug–drug interactions (DDIs). This study provides a whole‐body physiologically‐based pharmacokinetic/PD (PBPK/PD) model of S‐warfarin for predicting the effects of drug–drug−gene interactions on S‐warfarin PKs and PDs. The PBPK/PD model of S‐warfarin was developed in PK‐Sim and MoBi. Drug‐dependent parameters were obtained from the literature or optimized. Of the 34 S‐warfarin plasma concentration‐time profiles used, 96% predicted plasma concentrations within twofold range compared to observed data. For S‐warfarin plasma concentration‐time profiles with CYP2C9 genotype, 364 of 386 predicted plasma concentration values (~94%) fell within the twofold of the observed values. This model was tested in DDI predictions with fluconazole as CYP2C9 perpetrators, with all predicted DDI area under the plasma concentration‐time curve to the last measurable timepoint (AUClast) ratio within twofold of the observed values. The anticoagulant effect of S‐warfarin was described using an indirect response model, with all predicted international normalized ratio (INR) within twofold of the observed values. This model also incorporates a dose‐adjustment method that can be used for dose adjustment and predict INR when warfarin is used in combination with CYP2C9 perpetrators.

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Novel isomeric metabolite profiles correlate with warfarin metabolism phenotype during maintenance dosing in a pilot study of 29 patients

Cited by 5 publications

References 41 publications

Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin

Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin

Pharmacokinetic Modeling of Warfarin ІI – Model-Based Analysis of Warfarin Metabolites after Warfarin Administered Either Alone or Together with Fluconazole or Rifampin

A physiologically‐based pharmacokinetic/pharmacodynamic modeling approach for drug–drug‐gene interaction evaluation of S‐warfarin with fluconazole

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