Novel Cytochrome P450 Reaction Phenotyping for Low-Clearance Compounds Using the Hepatocyte Relay Method

Yang, Xin; Atkinson, Karen; Di, Li

doi:10.1124/dmd.115.067876

Cited by 41 publications

(41 citation statements)

References 25 publications

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“…Accordingly, these questions should be addressed by the malaria community using the various malaria animal models and controlled human clinical trials. Recent advances in in vitro drug metabolism and malaria infection models will hopefully allow for more complete and expedited investigations of such questions (Furuya, Sa, Chitnis, Wellems, & Stedman, 2014;Ng, et al, 2015;Yang, Atkinson, & Di, 2015).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art

Marcsisin

Reichard

Pybus

2016

Pharmacology & Therapeutics

105

104

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Primaquine is the only antimalarial drug available to clinicians for the treatment of relapsing forms of malaria. Primaquine development and usage dates back to the 1940s and has been administered to millions of individuals to treat and eliminate malaria infections. Primaquine therapy is not without disadvantages, however, as it can cause life threatening hemolysis in humans with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, the efficacy of primaquine against relapsing malaria was recently linked to CYP 2D6 mediated activation to an active metabolite, the structure of which has escaped definitive identification for over 75years. CYP 2D6 is highly polymorphic among various human populations adding further complexity to a comprehensive understanding of primaquine pharmacology. This review aims to discuss primaquine pharmacology in the context of state of the art understanding of CYP 2D6 mediated 8-aminoquinoline metabolic activation, and shed light on the current knowledge gaps of 8-aminoquinoline mechanistic understanding against relapsing malaria.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art

Marcsisin

Reichard

Pybus

2016

Pharmacology & Therapeutics

105

104

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“…Similarly, commonly used CYP2D6 inactivators (e.g. paroxetine) also demonstrate inhibition of CYP2B6 (Yang et al, ). If both CYP2B6 and CYP2D6 contribute to the clearance of a compound, it will be difficult to discern the f m between the two enzymes due to the inhibitor cross‐talk.…”

Section: Introductionmentioning

confidence: 98%

“…If there is cross‐talk of inhibitors among multiple enzymes, it will be challenging to estimate accurately f m and an over‐estimation of f m is likely. Typically, irreversible inhibitors are preferred over reversible inhibitors for reaction phenotyping to provide maximal knock‐out of the enzymes and to avoid the impact of inhibitor depletion during the long incubation for low clearance substrates (Yang, Atkinson, & Di, ), as the number of low clearance compounds continues to increase in drug discovery in order to achieve low doses and long half‐lives (Di et al, ; Di et al, ; Di & Obach, ). Although relatively selective inhibitors of many CYP enzymes are available (Bohnert et al, ; Di, ; Zientek & Youdim, ), the identification of CYP2B6‐specific inhibitors for reaction phenotyping has been challenging.…”

Section: Introductionmentioning

confidence: 99%

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Dasotraline as a selective cytochrome 2B6 inhibitor for reaction phenotyping

Yang

Ryu

2019

Biopharm & Drug Disp

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Reaction phenotyping using human liver microsomes or hepatocytes with chemical inhibitors is one of the most commonly applied methods to assess the fraction metabolized (fm) of drug candidates by enzymes. The fm information is critical to understanding the risk of victim drug–drug interactions in the clinic. Inhibitor selectivity is essential in order to generate reliable data and irreversible inhibitors are often preferred over reversible inhibitors to minimize the impact of inhibitor depletion. Although many selective cytochrome P450 (CYP) inhibitors are available, the identification of selective CYP2B6 inhibitors has been challenging due to cross inhibition to the other enzymes. In this study, dasotraline was evaluated as a selective inactivator of CYP2B6 under reaction phenotyping conditions with human hepatocytes. The results show that dasotraline is a very selective inactivator for CYP2B6 with minimal inhibition to other enzymes. A concentration of 0.1 μM dasotraline is recommended for reaction phenotyping with a hepatocyte cell density of 0.5 million cells/ml or 0.5 μM for 2 million cells/ml, when using a 15 minute preincubation, as well as the protocol of inactivator removal before the addition of substrates.

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“…Recently, approaches including the hepatocyte relay method ) and coculture models, such as HepatoPac or Hurel (Chan et al, 2013), have been evaluated and have shown promising results to better determine CL int via increasing the amount of substrate depletion or metabolite formation. Although these systems have gained considerable popularity in generating metabolites and determining intrinsic clearance of very low clearance compounds, the use of these models for phenotyping studies is under development (Yang et al, 2016).…”

Section: Special Considerations: Low Turnover Extrahepatic Metabolismentioning

confidence: 99%

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Bohnert¹,

Patel²,

Templeton³

et al. 2016

Drug Metabolism and Disposition

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Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (f CL ), estimation of fractional contribution of metabolizing enzyme toward metabolism (f m ), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify f CL and f m , 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.

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Novel Cytochrome P450 Reaction Phenotyping for Low-Clearance Compounds Using the Hepatocyte Relay Method

Cited by 41 publications

References 25 publications

Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art

Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art

Dasotraline as a selective cytochrome 2B6 inhibitor for reaction phenotyping

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

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