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Drug Metabolism and Disposition
Journal Prestige (SJR): 1.433  Citation Impact (citeScore): 4 Number of Followers: 11  Hybrid journal (It can contain Open Access articles)ISSN (Online) 1521-009X Published by ASPET  [4 journals]
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- Special Section on Perspectives on Drug Metabolism and Disposition, Part
I--Editorial [50th Anniversary Celebration Collection Special Section on
Perspectives on Drug Metabolism and Disposition, Part I-Editorial]-
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Authors: Lai, Y; Ding, X.
Pages: 645 - 646
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.123.001352
Issue No: Vol. 51, No. 6 (2023)
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- Human Absorption, Distribution, Metabolism, and Excretion Studies:
Origins, Innovations, and Importance [50th Anniversary Celebration
Collection Special Section on Perspective on Drug Metabolism and
Disposition, Part I-Minireview]-
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Authors: Cerny, M. A; Spracklin, D. K, Obach, R. S.
Pages: 647 - 656
Abstract: Human absorption, distribution, metabolism, and excretion (hADME) studies represent one of the most important clinical studies in terms of obtaining a comprehensive and quantitative overview of the total disposition of a drug. This article will provide background on the origins of hADME studies as well as provide an overview of technological innovations that have impacted how hADME studies are carried out and analyzed. An overview of the current state of the art for hADME studies will be provided, the impacts of advances in technology and instrumentation on the timing of and approaches to hADME studies will be discussed, and a summary of the parameters and information obtained from these studies will be offered. Additionally, aspects of the ongoing debate over the importance of animal absorption, distribution, metabolism, and excretion studies versus a "human-first, human-only strategy" will be presented. Along with the information above, this manuscript will highlight how, for over 50 years, Drug Metabolism and Disposition has served as an important outlet for the reporting of hADME studies.SIGNIFICANCE STATEMENTHuman absorption, distribution, metabolism, and excretion (hADME) studies have and will continue to be important to the understanding and development of drugs. This manuscript provides a historical perspective on the origins of hADME studies as well as advancements resulting in the current-state-of the art practice for these studies.
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.122.001006
Issue No: Vol. 51, No. 6 (2023)
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- Fifty Years of Aryl Hydrocarbon Receptor Research as Reflected in the
Pages of Drug Metabolism and Disposition [50th Anniversary Celebration
Collection Special Section on Perspective on Drug Metabolism and
Disposition, Part I-Minireview]-
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Authors: Riddick D. S.
Pages: 657 - 671
Abstract: The induction of multiple drug-metabolizing enzymes by halogenated and polycyclic aromatic hydrocarbon toxicants is mediated by the aryl hydrocarbon receptor (AHR). This fascinating receptor also has natural dietary and endogenous ligands, and much is now appreciated about the AHR’s developmental and physiologic roles, as well as its importance in cancer and other diseases. The past several years has witnessed increasing emphasis on understanding the multifaceted roles of the AHR in the immune system. Most would agree that the "discovery" of the AHR occurred in 1976, with the report of specific binding of a high affinity radioligand in mouse liver, just three years after the launch of the journal Drug Metabolism and Disposition (DMD) in 1973. Over the ensuing 50 years, the AHR and DMD have led parallel and often intersecting lives. The overall goal of this mini-review is to provide a decade-by-decade overview of major historical landmark discoveries in the AHR field and to highlight the numerous contributions made by publications appearing in the pages of DMD. It is hoped that this historical tour might inspire current and future research in the AHR field.SIGNIFICANCE STATEMENTWith the launch of Drug Metabolism and Disposition (DMD) in 1973 and the discovery of the aryl hydrocarbon receptor (AHR) in 1976, the journal and the receptor have led parallel and often intersecting lives over the past 50 years. Tracing the history of the AHR can reveal how knowledge in the field has evolved to the present and highlight the important contributions made by discoveries reported in DMD. This may inspire additional DMD papers reporting future AHR landmark discoveries.
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.122.001009
Issue No: Vol. 51, No. 6 (2023)
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- Epigenetic Mechanisms Contribute to Intraindividual Variations of Drug
Metabolism Mediated by Cytochrome P450 Enzymes [50th Anniversary
Celebration Collection Special Section on Perspective on Drug Metabolism
and Disposition, Part I-Minireview]-
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Authors: Jin, J; Zhong, X.-b.
Pages: 672 - 684
Abstract: Significant interindividual and intraindividual variations on cytochrome P450 (CYP)-mediated drug metabolism exist in the general population globally. Genetic polymorphisms are one of the major contribution factors for interindividual variations, but epigenetic mechanisms mainly contribute to intraindividual variations, including DNA methylation, histone modifications, microRNAs, and long non-coding RNAs. The current review provides analysis of advanced knowledge in the last decade on contributions of epigenetic mechanisms to intraindividual variations on CYP-mediated drug metabolism in several situations, including (1) ontogeny, the developmental changes of CYP expression in individuals from neonates to adults; (2) increased activities of CYP enzymes induced by drug treatment; (3) increased activities of CYP enzymes in adult ages induced by drug treatment at neonate ages; and (4) decreased activities of CYP enzymes in individuals with drug-induced liver injury (DILI). Furthermore, current challenges, knowledge gaps, and future perspective of the epigenetic mechanisms in development of CYP pharmacoepigenetics are discussed. In conclusion, epigenetic mechanisms have been proven to contribute to intraindividual variations of drug metabolism mediated by CYP enzymes in age development, drug induction, and DILI conditions. The knowledge has helped understanding how intraindividual variation are generated. Future studies are needed to develop CYP-based pharmacoepigenetics to guide clinical applications for precision medicine with improved therapeutic efficacy and reduced risk of adverse drug reactions and toxicity.SIGNIFICANCE STATEMENTUnderstanding epigenetic mechanisms in contribution to intraindividual variations of CYP-mediated drug metabolism may help to develop CYP-based pharmacoepigenetics for precision medicine to improve therapeutic efficacy and reduce adverse drug reactions and toxicity for drugs metabolized by CYP enzymes.
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.122.001007
Issue No: Vol. 51, No. 6 (2023)
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- Recombinant Technologies Facilitate Drug Metabolism, Pharmacokinetics, and
General Biomedical Research [50th Anniversary Celebration Collection
Special Section on Perspective on Drug Metabolism and Disposition, Part
I-Minireview]-
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Authors: Cronin, J. M; Yu, A.-M.
Pages: 685 - 699
Abstract: The development of safe and effective medications requires a profound understanding of their pharmacokinetic (PK) and pharmacodynamic properties. PK studies have been built through investigation of enzymes and transporters that drive drug absorption, distribution, metabolism, and excretion (ADME). Like many other disciplines, the study of ADME gene products and their functions has been revolutionized through the invention and widespread adoption of recombinant DNA technologies. Recombinant DNA technologies use expression vectors such as plasmids to achieve heterologous expression of a desired transgene in a specified host organism. This has enabled the purification of recombinant ADME gene products for functional and structural characterization, allowing investigators to elucidate their roles in drug metabolism and disposition. This strategy has also been used to offer recombinant or bioengineered RNA (BioRNA) agents to investigate the posttranscriptional regulation of ADME genes. Conventional research with small noncoding RNAs such as microRNAs (miRNAs) and small interfering RNAs has been dependent on synthetic RNA analogs that are known to carry a range of chemical modifications expected to improve stability and PK properties. Indeed, a novel transfer RNA fused pre-miRNA carrier-based bioengineering platform technology has been established to offer consistent and high-yield production of unparalleled BioRNA molecules from Escherichia coli fermentation. These BioRNAs are produced and processed inside living cells to better recapitulate the properties of natural RNAs, representing superior research tools to investigate regulatory mechanisms behind ADME.SIGNIFICANCE STATEMENTThis review article summarizes recombinant DNA technologies that have been an incredible boon in the study of drug metabolism and PK, providing investigators with powerful tools to express nearly any ADME gene products for functional and structural studies. It further overviews novel recombinant RNA technologies and discusses the utilities of bioengineered RNA agents for the investigation of ADME gene regulation and general biomedical research.
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.122.001008
Issue No: Vol. 51, No. 6 (2023)
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- Impact of Intracellular Lipid Binding Proteins on Endogenous and
Xenobiotic Ligand Metabolism and Disposition [50th Anniversary Celebration
Collection Special Section on Perspective in Drug Metabolism and
Disposition, Part I-Minireview]-
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Authors: Yabut, K. C. B; Isoherranen, N.
Pages: 700 - 717
Abstract: The family of intracellular lipid binding proteins (iLBPs) is comprised of 16 members of structurally related binding proteins that have ubiquitous tissue expression in humans. iLBPs collectively bind diverse essential endogenous lipids and xenobiotics. iLBPs solubilize and traffic lipophilic ligands through the aqueous milieu of the cell. Their expression is correlated with increased rates of ligand uptake into tissues and altered ligand metabolism. The importance of iLBPs in maintaining lipid homeostasis is well established. Fatty acid binding proteins (FABPs) make up the majority of iLBPs and are expressed in major organs relevant to xenobiotic absorption, distribution, and metabolism. FABPs bind a variety of xenobiotics including nonsteroidal anti-inflammatory drugs, psychoactive cannabinoids, benzodiazepines, antinociceptives, and peroxisome proliferators. FABP function is also associated with metabolic disease, making FABPs currently a target for drug development. Yet the potential contribution of FABP binding to distribution of xenobiotics into tissues and the mechanistic impact iLBPs may have on xenobiotic metabolism are largely undefined. This review examines the tissue-specific expression and functions of iLBPs, the ligand binding characteristics of iLBPs, their known endogenous and xenobiotic ligands, methods for measuring ligand binding, and mechanisms of ligand delivery from iLBPs to membranes and enzymes. Current knowledge of the importance of iLBPs in affecting disposition of xenobiotics is collectively described.SIGNIFICANCE STATEMENTThe data reviewed here show that FABPs bind many drugs and suggest that binding of drugs to FABPs in various tissues will affect drug distribution into tissues. The extensive work and findings with endogenous ligands suggest that FABPs may also alter the metabolism and transport of drugs. This review illustrates the potential significance of this understudied area.
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.122.001010
Issue No: Vol. 51, No. 6 (2023)
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- Combined Oral Contraceptives As Victims of Drug Interactions [50th
Anniversary Celebration Collection-Minireview]-
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Authors: Li, L; Yang, X, Tran, D, Seo, S. K, Lu, Y.
Pages: 718 - 732
Abstract: Combined oral contraceptives (COCs) are widely used in women of reproductive age in the United States. Metabolism plays an important role in the elimination of estrogens and progestins contained in COCs. It is unavoidable that a woman using COCs may need to take another drug to treat a disease. If the concurrently used drug induces enzymes responsible for the metabolism of progestins and/or estrogens, unintended pregnancy or irregular bleeding may occur. If the concurrent drug inhibits the metabolism of these exogenous hormones, there may be an increased safety risk such as thrombosis. Therefore, for an investigational drug intended to be used in women with reproductive potential, evaluating its effects on the pharmacokinetics of COCs is important to determine if additional labeling is necessary for managing drug-drug interactions (DDIs) between the concomitant product and the COCs. It is challenging to determine when this clinical drug interaction study is needed, whether an observed exposure change of progestin/estrogen is clinically meaningful, and if the results of a clinical drug interaction study with one COC can predict exposure changes of unstudied COCs to inform labeling. In this review, we summarize the current understanding of metabolic pathways of estrogens and progestins contained in commonly used COCs and known interactions of these COCs as victim drugs and we discuss possible mechanisms of interactions for unexpected results. We also discuss recent advances, knowledge gaps, and future perspectives on this important topic. The review will enhance the understanding of DDIs with COCs and improve the safe and effective use of COCs.SIGNIFICANCE STATEMENTThis minireview provides an overview of the metabolic pathways of ethinyl estradiol and progestins contained in commonly used combined oral contraceptives (COCs) and significant drug interactions of these COCs as victims. It also discusses recent advances, knowledge gaps, future perspectives, and potential mechanisms for unexpected results of clinical drug interaction studies of COCs. This minireview will help the reader understand considerations when evaluating the drug interaction potential with COCs for drugs that are expected to be used concurrently.
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.122.000854
Issue No: Vol. 51, No. 6 (2023)
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- Characterization of Enzymes Involved in Nintedanib Metabolism in Humans
[Article]-
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Authors: Nakashima, S; Sato, R, Fukami, T, Kudo, T, Hashiba, S, Morinaga, G, Nakano, M, Ludwig-Schwellinger, E, Matsui, A, Ishiguro, N, Ebner, T, Nakajima, M.
Pages: 733 - 742
Abstract: Nintedanib, which is used to treat idiopathic pulmonary fibrosis and non–small cell lung cancer, is metabolized to a pharmacologically inactive carboxylate derivative, BIBF1202, via hydrolysis and subsequently by glucuronidation to BIBF1202 acyl-glucuronide (BIBF1202-G). Since BIBF1202-G contains an ester bond, it can be hydrolytically cleaved to BIBF1202. In this study, we sought to characterize these metabolic reactions in the human liver and intestine. Nintedanib hydrolysis was detected in human liver microsomes (HLMs) (Clearance [CLint]: 102.8 ± 18.9 µL/min per mg protein) but not in small intestinal preparations. CES1 was suggested to be responsible for nintedanib hydrolysis according to experiments using recombinant hydrolases and hydrolase inhibitors as well as proteomic correlation analysis using 25 individual HLM. BIBF1202 glucuronidation in HLM (3.6 ± 0.3 µL/min per mg protein) was higher than that in human intestinal microsomes (1.5 ± 0.06 µL/min per mg protein). UGT1A1 and gastrointestinal UGT1A7, UGT1A8, and UGT1A10 were able to mediate BIBF1202 glucuronidation. The impact of UGT1A1 on glucuronidation was supported by the finding that liver microsomes from subjects homozygous for the UGT1A1*28 allele showed significantly lower activity than those from subjects carrying the wild-type UGT1A1 allele. Interestingly, BIBF1202-G was converted to BIBF1202 in HLS9 at 70-fold higher rates than the rates of BIBF1202 glucuronidation. An inhibition study and proteomic correlation analysis suggested that β-glucuronidase is responsible for hepatic BIBF1202-G deglucuronidation. In conclusion, the major metabolic reactions of nintedanib in the human liver and intestine were quantitatively and thoroughly elucidated. This information could be helpful to understand the inter- and intraindividual variability in the efficacy of nintedanib.SIGNIFICANCE STATEMENTTo our knowledge, this is the first study to characterize the enzymes responsible for each step of nintedanib metabolism in the human body. This study found that β-glucuronidase may contribute to BIBF1202-G deglucuronidation.
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.122.001113
Issue No: Vol. 51, No. 6 (2023)
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- A Physiologically-Based Pharmacokinetic Model for Cannabidiol in Healthy
Adults, Hepatically-Impaired Adults, and Children [Article]-
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Authors: Bansal, S; Ladumor, M. K, Paine, M. F, Unadkat, J. D.
Pages: 743 - 752
Abstract: Cannabidiol (CBD) is available as a prescription oral drug that is indicated for the treatment of some types of epilepsy in children and adults. CBD is also available over-the-counter and is used to self-treat a variety of other ailments, including pain, anxiety, and insomnia. Accordingly, CBD may be consumed with other medications, resulting in possible CBD-drug interactions. Such interactions can be predicted in healthy and hepatically-impaired (HI) adults and in children through physiologically based pharmacokinetic (PBPK) modeling and simulation. These PBPK models must be populated with CBD-specific parameters, including the enzymes that metabolize CBD in adults. In vitro reaction phenotyping experiments showed that UDP-glucuronosyltransferases (UGTs, 80%), particularly UGT2B7 (64%), were the major contributors to CBD metabolism in adult human liver microsomes. Among the cytochrome P450s (CYPs) tested, CYP2C19 (5.7%) and CYP3A (6.5%) were the major CYPs responsible for CBD metabolism. Using these and other physicochemical parameters, a CBD PBPK model was developed and validated for healthy adults. This model was then extended to predict CBD systemic exposure in HI adults and children. Our PBPK model successfully predicted CBD systemic exposure in both populations within 0.5- to 2-fold of the observed values. In conclusion, we developed and validated a PBPK model to predict CBD systemic exposure in healthy and HI adults and children. This model can be used to predict CBD-drug or CBD-drug-disease interactions in these populations.SIGNIFICANCE STATEMENTOur PBPK model successfully predicted CBD systemic exposure in healthy and hepatically-impaired adults, as well as children with epilepsy. This model could be used in the future to predict CBD-drug or CBD-drug-disease interactions in these special populations.
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.122.001128
Issue No: Vol. 51, No. 6 (2023)
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- Complex Metabolism of the Novel Neurosteroid, Ganaxolone, in Humans: A
Unique Challenge for Metabolites in Safety Testing Assessment [Article]-
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Authors: Fitch, W. L; Smith, S, Saporito, M, Busse, G, Zhang, M, Ren, J, Fitzsimmons, M. E, Yi, P, English, S, Carter, A, Baillie, T. A.
Pages: 753 - 763
Abstract: The human pharmacokinetics, metabolism, and excretion of [14C]-ganaxolone (GNX) were characterized in healthy male subjects (n = 8) following a single 300-mg (150 μCi) oral dose. GNX exhibited a short half-life of 4 hours in plasma, whereas total radioactivity had a half-life of 413 hours indicating extensive metabolism to long-lived metabolites. Identification of the major GNX circulating metabolites required extensive isolation and purification for liquid chromatography-tandem mass spectrometry analysis, together with in vitro studies, NMR spectroscopy, and synthetic chemistry support. This revealed that the major routes of GNX metabolism involved hydroxylation at the 16α-hydroxy position, stereoselective reduction of the 20-ketone to afford the corresponding 20α-hydroxysterol, and sulfation of the 3α-hydroxy group. This latter reaction yielded an unstable tertiary sulfate, which eliminated the elements of H2SO4 to introduce a double bond in the A ring. A combination of these pathways, together with oxidation of the 3β-methyl substituent to a carboxylic acid and sulfation at the 20α position, led to the major circulating metabolites in plasma, termed M2 and M17. These studies, which led to the complete or partial identification of no less than 59 metabolites of GNX, demonstrated the high complexity of the metabolic fate of this drug in humans and demonstrated that the major circulating products in plasma can result from multiple sequential processes that may not be easily replicated in animals or with animal or human in vitro systems.SIGNIFICANCE STATEMENTStudies on the metabolism of [14C]-ganaxolone in humans revealed a complex array of products that circulated in plasma, the two major components of which were formed via an unexpected multi-step pathway. Complete structural characterization of these (disproportionate) human metabolites required extensive in vitro studies, along with contemporary mass spectrometry, NMR spectroscopy, and synthetic chemistry efforts, which served to underscore the limitations of traditional animal studies in predicting major circulating metabolites in man.
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.122.001218
Issue No: Vol. 51, No. 6 (2023)
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- Inactivation of Human Aldehyde Oxidase by Small Sulfhydryl-Containing
Reducing Agents [Article]-
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Authors: Esmaeeli, M; Nimtz, M, Jänsch, L, Ruddock, L. W, Leimkühler, S.
Pages: 764 - 770
Abstract: Human aldehyde oxidase (hAOX1) is a molybdoflavoenzyme that belongs to the xanthine oxidase (XO) family. hAOX1 is involved in phase I drug metabolism, but its physiologic role is not fully understood to date, and preclinical studies consistently underestimated hAOX1 clearance. In the present work, we report an unexpected effect of the common sulfhydryl-containing reducing agents, e.g., dithiothreitol (DTT), on the activity of hAOX1 and mouse aldehyde oxidases. We demonstrate that this effect is due to the reactivity of the sulfido ligand bound at the molybdenum cofactor with the sulfhydryl groups. The sulfido ligand coordinated to the Mo atom in the XO family of enzymes plays a crucial role in the catalytic cycle and its removal results in the total inactivation of these enzymes. Because liver cytosols, S9 fractions, and hepatocytes are commonly used to screen the drug candidates for hAOX1, our study suggests that DTT treatment of these samples should be avoided, otherwise false negative results by an inactivated hAOX1 might be obtained.SIGNIFICANCE STATEMENTThis work characterizes the inactivation of human aldehyde oxidase (hAOX1) by sulfhydryl-containing agents and identifies the site of inactivation. The role of dithiothreitol in the inhibition of hAOX1 should be considered for the preparation of hAOX1-containing fractions for pharmacological studies on drug metabolism and drug clearance.
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.122.001244
Issue No: Vol. 51, No. 6 (2023)
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- Mechanistic Study of Icaritin-Induced Inactivation of Cytochrome P450 2C9
[Article]-
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Authors: Chen, X; Han, L, Zhao, Y, Huang, H, Pan, H, Zhang, C, Chen, H, Sun, S, Yao, S, Chen, X, Zhang, Y.
Pages: 771 - 781
Abstract: Icaritin (ICT) is a prenylflavonoid derivative that has been approved by National Medical Products Administration for the treatment of hepatocellular carcinoma. This study aims to evaluate the potential inhibitory effect of ICT against cytochrome P450 (CYP) enzymes and to elucidate the inactivation mechanisms. Results showed that ICT inactivated CYP2C9 in a time-, concentration-, and NADPH-dependent manner with Ki = 1.896 μM, Kinact = 0.02298 minutes–1, and Kinact/Ki = 12 minutes–1 mM–1, whereas the activities of other CYP isozymes was minimally affected. Additionally, the presence of CYP2C9 competitive inhibitor, sulfaphenazole, superoxide dismutase/catalase system, and GSH all protected CYP2C9 from ICT-induced activity loss. Moreover, the activity loss was neither recovered by washing the ICT-CYP2C9 preincubation mixture nor the addition of potassium ferricyanide. These results, collectively, implied the underlying inactivation mechanism involved the covalent binding of ICT to the apoprotein and/or the prosthetic heme of CYP2C9. Furthermore, an ICT-quinone methide (QM)-derived GSH adduct was identified, and human glutathione S-transferases (GST) isozymes GSTA1-1, GSTM1-1, and GSTP1-1 were shown to be substantially involved in the detoxification of ICT-QM. Interestingly, our systematic molecular modeling work predicted that ICT-QM was covalently bound to C216, a cysteine residue located in the F-G loop downstream of substrate recognition site (SRS) 2 in CYP2C9. The sequential molecular dynamics simulation confirmed the binding to C216 induced a conformational change in the active catalytic center of CYP2C9. Lastly, the potential risks of clinical drug-drug interactions triggered by ICT as a perpetrator were extrapolated. In summary, this work confirmed that ICT was an inactivator of CYP2C9.SIGNIFICANCE STATEMENTThis study is the first to report the time-dependent inhibition of CYP2C9 by icaritin (ICT) and the intrinsic molecular mechanism behind it. Experimental data indicated that the inactivation was via irreversible covalent binding of ICT-quinone methide to CYP2C9, while molecular modeling analysis provided additional evidence by predicting C216 as the key binding site which influenced the structural confirmation of CYP2C9’s catalytic center. These findings suggest the potential of drug–drug interactions when ICT is co-administered with CYP2C9 substrates clinically.
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.122.001245
Issue No: Vol. 51, No. 6 (2023)
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- Mechanistic Investigation of the Time-Dependent Aldehyde Oxidase Inhibitor
Hydralazine [Article]-
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Authors: Barnes, J. P; Yang, S. M, Thompson, T. S, Guevarra, C. M, Pleasant, S. S, Do, T. Q, Crouch, R. D.
Pages: 782 - 791
Abstract: The anti-hypertensive agent hydralazine is a time-dependent inhibitor of the cytosolic drug-metabolizing enzyme aldehyde oxidase (AO). Glutathione (GSH) was found to suppress the inhibition of AO by hydralazine in multiple enzyme sources (human liver and kidney cytosol, human liver S9, rat liver S9, and recombinant human AO) and with different AO substrates (zoniporide, O6-benzylguanine, and dantrolene). Hydralazine-induced AO inactivation was unaffected when GSH was added to the incubation mixture after pre-incubation of hydralazine with AO (rather than during the pre-incubation), suggesting that GSH traps a hydralazine reactive intermediate prior to enzyme inactivation. Consistent with previous reports of 1-phthalazylmercapturic acid formation when hydralazine was incubated with N-acetylcysteine, we detected a metabolite producing an MS/MS spectrum consistent with a 1-phthalazyl-GSH conjugate. O6-Benzylguanine, an AO substrate, did not protect against hydralazine-induced AO inactivation, implying that hydralazine does not compete with O6-benzylguanine for binding to the AO active site. Catalase also failed to protect AO from hydralazine-induced inactivation, suggesting that hydrogen peroxide is not involved. However, an allosteric AO inhibitor (thioridazine) offered some protection, indicating a catalytic role for AO in the bioactivation of hydralazine. AO inhibition by phthalazine (a substrate and inhibitor of AO and a metabolite of hydralazine) was unaffected by the presence of GSH. GSH also prevented hydralazine from inhibiting the nitro-reduction of dantrolene by AO. Furthermore, the GSH-hydralazine combination stimulated dantrolene reduction. Phthalazine inhibited only oxidation reactions, not reduction of dantrolene. Together, these results support the hypothesis that hydralazine is converted to a reactive intermediate that inactivates AO.SIGNIFICANCE STATEMENTThese studies suggest that a reactive intermediate of hydralazine plays a primary role in the mechanism of aldehyde oxidase (AO) inactivation. Inactivation was attenuated by glutathione and unaffected by catalase. Phthalazine (hydralazine metabolite) inhibited AO regardless of the presence of glutathione; however, phthalazine inhibited only oxidation reactions, while hydralazine inhibited both oxidation and reduction reactions. This report advances our mechanistic understanding of hydralazine as an AO inhibitor and provides information to facilitate appropriate use of hydralazine when probing AO metabolism.
PubDate: 2023-05-11T07:46:30-07:00
DOI: 10.1124/dmd.123.001257
Issue No: Vol. 51, No. 6 (2023)
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