Biotransformation novel advances – 2021 year in review

Abstract Biotransformation field is constantly evolving with new molecular structures and discoveries of metabolic pathways that impact efficacy and safety. Recent review by Kramlinger et al. (2022) nicely captures the future (and the past) of highly impactful science of biotransformation (see the first article). Based on the selected articles, this review was categorized into three sections: (1) new modalities biotransformation, (2) drug discovery biotransformation, and (3) drug development biotransformation (Table 1).

[1]  K. Yoshinari,et al.  CYP2C8-Mediated Formation of a Human Disproportionate Metabolite of the Selective NaV1.7 Inhibitor DS-1971a, a Mixed Cytochrome P450 and Aldehyde Oxidase Substrate , 2021, Drug Metabolism and Disposition.

[2]  A. Kalgutkar,et al.  Future of Biotransformation Science in the Pharmaceutical Industry , 2021, Drug Metabolism and Disposition.

[3]  Cordula Stillhart,et al.  Addressing Today’s Absorption, Distribution, Metabolism, and Excretion (ADME) Challenges in the Translation of In Vitro ADME Characteristics to Humans: A Case Study of the SMN2 mRNA Splicing Modifier Risdiplam , 2021, Drug Metabolism and Disposition.

[4]  P. Espenshade,et al.  Progesterone receptor membrane component 1 (PGRMC1) binds and stabilizes cytochromes P450 through a heme-independent mechanism , 2021, The Journal of biological chemistry.

[5]  K. Yoshinari,et al.  Evaluation of species differences in the metabolism of the selective NaV1.7 inhibitor DS-1971a, a mixed substrate of cytochrome P450 and aldehyde oxidase , 2021, Xenobiotica; the fate of foreign compounds in biological systems.

[6]  R. Obach,et al.  Static and Dynamic Projections of Drug-Drug Interactions Caused by Cytochrome P450 3A Time-Dependent Inhibitors Measured in Human Liver Microsomes and Hepatocytes , 2021, Drug Metabolism and Disposition.

[7]  Jangir Selimkhanov,et al.  Contribution of Extrahepatic Aldehyde Oxidase Activity to Human Clearance , 2021, Drug Metabolism and Disposition.

[8]  M. Manoharan,et al.  The Nonclinical Disposition and Pharmacokinetic/Pharmacodynamic Properties of N-Acetylgalactosamine–Conjugated Small Interfering RNA Are Highly Predictable and Build Confidence in Translation to Human , 2021, Drug Metabolism and Disposition.

[9]  V. Shanmugasundaram,et al.  Investigation into MAO B–Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B , 2021, Drug Metabolism and Disposition.

[10]  G. Miller,et al.  Novel advances in biotransformation and bioactivation research – 2020 year in review , 2021, Drug metabolism reviews.

[11]  Peijin Zhang,et al.  Absorption, Metabolism, and Excretion, In Vitro Pharmacology, and Clinical Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator , 2021, Drug Metabolism and Disposition.

[12]  J. Uetrecht,et al.  Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges , 2021, International journal of molecular sciences.

[13]  E. Mercuri,et al.  Risdiplam in Type 1 Spinal Muscular Atrophy. , 2021, The New England journal of medicine.

[14]  Yan-Ling He,et al.  Pharmacokinetics, metabolism, and excretion of licogliflozin, a dual inhibitor of SGLT1/2, in rats, dogs, and humans , 2021, Xenobiotica; the fate of foreign compounds in biological systems.

[15]  A. Laurenza,et al.  In Vitro Metabolism of Slowly Cleared G Protein–Coupled Receptor 139 Agonist TAK-041 Using Rat, Dog, Monkey, and Human Hepatocyte Models (HepatoPac): Correlation with In Vivo Metabolism , 2020, Drug Metabolism and Disposition.

[16]  Kaori Matsumoto,et al.  Role of human flavin-containing monooxygenase (FMO) 5 in the metabolism of nabumetone: Baeyer–Villiger oxidation in the activation of the intermediate metabolite, 3-hydroxy nabumetone, to the active metabolite, 6-methoxy-2-naphthylacetic acid in vitro , 2020, Xenobiotica; the fate of foreign compounds in biological systems.

[17]  Peijin Zhang,et al.  Multiple-Dose Pharmacokinetics of Ozanimod and its Major Active Metabolites and the Pharmacodynamic and Pharmacokinetic Interactions with Pseudoephedrine, a Sympathomimetic Agent, in Healthy Subjects , 2020, Advances in Therapy.

[18]  S. Heyward,et al.  CHARACTERIZATION OF DIFFERENTIAL TISSUE ABUNDANCE OF MAJOR NON-CYP ENZYMES IN HUMAN. , 2020, Molecular pharmaceutics.

[19]  K. Schroer,et al.  Absorption, Distribution, Metabolism, and Excretion of Capmatinib (INC280) in Healthy Male Volunteers and In Vitro Aldehyde Oxidase Phenotyping of the Major Metabolite , 2020, Drug Metabolism and Disposition.

[20]  J. Beijnen,et al.  Extrahepatic metabolism of ibrutinib , 2020, Investigational New Drugs.

[21]  Thomas Eric Ballard,et al.  Simplifying the Execution of HepatoPac MetID Experiments: Metabolite Profile and Intrinsic Clearance Comparisons , 2020, Drug Metabolism and Disposition.

[22]  G. Miller,et al.  Novel advances in biotransformation and bioactivation research—2019 year in review , 2020, Drug metabolism reviews.

[23]  R. Obach,et al.  Cytochrome P450 3A Time-Dependent Inhibition Assays Are Too Sensitive for Identification of Drugs Causing Clinically Significant Drug-Drug Interactions: A Comparison of Human Liver Microsomes and Hepatocytes and Definition of Boundaries for Inactivation Rate Constants , 2020, Drug Metabolism and Disposition.

[24]  R. Koishi,et al.  Discovery of DS-1971a, a Potent Selective NaV1.7 Inhibitor. , 2020, Journal of medicinal chemistry.

[25]  Sara C. Humphreys,et al.  Emerging siRNA design principles and consequences for biotransformation and disposition in drug development. , 2020, Journal of medicinal chemistry.

[26]  H. Bian.  The Nature of Drugs , 2020, Know Your Remedies.

[27]  P. Sengupta,et al.  A neurotransmitter produced by gut bacteria modulates host sensory behaviour , 2020, Nature.

[28]  V. Goel,et al.  Pharmacokinetics and Pharmacodynamics of the Small Interfering Ribonucleic Acid, Givosiran, in Patients With Acute Hepatic Porphyria , 2020, Clinical pharmacology and therapeutics.

[29]  C. Mantzoros,et al.  Obeticholic acid for the treatment of nonalcoholic steatohepatitis: expectations and concerns. , 2020, Metabolism: clinical and experimental.

[30]  Kaori Matsumoto,et al.  A metabolic pathway for the prodrug nabumetone to the pharmacologically active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA) by non-cytochrome P450 enzymes , 2019, Xenobiotica; the fate of foreign compounds in biological systems.

[31]  B. Laffitte,et al.  Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non–Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers , 2019, Clinical pharmacology in drug development.

[32]  Doyoung Kwon,et al.  Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications , 2019, Acta pharmaceutica Sinica. B.

[33]  R. Waring.  Cytochrome P450: genotype to phenotype , 2019, Xenobiotica; the fate of foreign compounds in biological systems.

[34]  W. Pitt,et al.  Metabolism by aldehyde oxidase: drug design and complementary approaches to challenges in drug discovery. , 2019, Journal of medicinal chemistry.

[35]  S. Chong,et al.  In Vitro Drug-Drug Interaction Evaluation of GalNAc Conjugated siRNAs Against CYP450 Enzymes and Transporters , 2019, Drug Metabolism and Disposition.

[36]  M. Ingelman-Sundberg,et al.  3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications , 2019, Biotechnology journal.

[37]  P. McNamara,et al.  Tropifexor‐Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With the Antioxidative Gene Expression Profile in Rodents , 2019, Hepatology communications.

[38]  G. Miller,et al.  Biotransformation and bioactivation reactions – 2018 literature highlights , 2019, Drug metabolism reviews.

[39]  E. Nevedomskaya,et al.  Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models , 2019, International journal of cancer.

[40]  Mai B. Thayer,et al.  Application of Locked Nucleic Acid Oligonucleotides for siRNA Preclinical Bioanalytics , 2019, Scientific Reports.

[41]  Jeffrey P. Jones,et al.  Time Course of Aldehyde Oxidase and Why It Is Nonlinear , 2019, Drug Metabolism and Disposition.

[42]  Michael Zimmermann,et al.  Separating host and microbiome contributions to drug pharmacokinetics and toxicity , 2019, Science.

[43]  E. Mercuri,et al.  The oral splicing modifier RG7800 increases full length survival of motor neuron 2 mRNA and survival of motor neuron protein: Results from trials in healthy adults and patients with spinal muscular atrophy , 2019, Neuromuscular Disorders.

[44]  A. Keshavarzian,et al.  Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease , 2019, Nature Communications.

[45]  T. Bergauer,et al.  A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier , 2018, British journal of clinical pharmacology.

[46]  Goonaseelan Pillai,et al.  The Next Generation Scientist program: capacity-building for future scientific leaders in low- and middle-income countries , 2018, BMC Medical Education.

[47]  G. S. Walker,et al.  An Ex Vivo Fermentation Screening Platform to Study Drug Metabolism by Human Gut Microbiota , 2018, Drug Metabolism and Disposition.

[48]  Michael Reutlinger,et al.  Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). , 2018, Journal of medicinal chemistry.

[49]  G. Miller,et al.  Biotransformation and bioactivation reactions – 2017 literature highlights** , 2018, Drug metabolism reviews.

[50]  W. Humphreys,et al.  A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the “Metabolites in Safety Testing” Regulatory Guidance , 2018, Drug Metabolism and Disposition.

[51]  R. Dick.  Refinement of In Vitro Methods for Identification of Aldehyde Oxidase Substrates Reveals Metabolites of Kinase Inhibitors , 2018, Drug Metabolism and Disposition.

[52]  L. Johannes,et al.  Current Challenges in Delivery and Cytosolic Translocation of Therapeutic RNAs , 2018, Nucleic acid therapeutics.

[53]  P. Klimko,et al.  Genotoxicity of 4-(piperazin-1-yl)-8-(trifluoromethyl)pyrido[2,3-e][1,2,4] triazolo[4,3-a]pyrazine, a Potent H4 Receptor Antagonist for the Treatment of Allergy: Evidence of Glyoxal Intermediate Involvement. , 2018, Drug metabolism letters.

[54]  P. McNamara,et al.  Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH). , 2017, Journal of medicinal chemistry.

[55]  K. G. Rajeev,et al.  Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc–siRNA conjugates , 2017, Nucleic acids research.

[56]  S. Leimkühler,et al.  Direct Comparison of the Enzymatic Characteristics and Superoxide Production of the Four Aldehyde Oxidase Enzymes Present in Mouse , 2017, Drug Metabolism and Disposition.

[57]  Ashish Ranjan Sharma,et al.  Therapeutic miRNA and siRNA: Moving from Bench to Clinic as Next Generation Medicine , 2017, Molecular therapy. Nucleic acids.

[58]  G. Miller,et al.  Biotransformation and bioactivation reactions – 2016 literature highlights , 2017, Drug metabolism reviews.

[59]  J. Manautou,et al.  Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity. , 2016, Pharmacological research.

[60]  S. Henry,et al.  Elucidation of the Biotransformation Pathways of a Galnac3-conjugated Antisense Oligonucleotide in Rats and Monkeys , 2016, Molecular therapy. Nucleic acids.

[61]  T. Baillie,et al.  Biotransformation and bioactivation reactions – 2015 literature highlights , 2016, Drug metabolism reviews.

[62]  Amy E. Chadwick,et al.  Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile , 2016, Archives of Toxicology.

[63]  M. Romão,et al.  Structure and function of mammalian aldehyde oxidases , 2016, Archives of Toxicology.

[64]  M. Behlke,et al.  Cellular localization of long non-coding RNAs affects silencing by RNAi more than by antisense oligonucleotides , 2015, Nucleic acids research.

[65]  J. Lieberman,et al.  Knocking down disease: a progress report on siRNA therapeutics , 2015, Nature Reviews Genetics.

[66]  Judy Lieberman,et al.  Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown , 2015, Nature Biotechnology.

[67]  J. Palvimo,et al.  Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies , 2015, Scientific Reports.

[68]  N. Hanioka,et al.  Species and sex differences in propofol glucuronidation in liver microsomes of humans, monkeys, rats and mice. , 2015, Die Pharmazie.

[69]  Y. Shibata,et al.  The Role of Extrahepatic Metabolism in the Pharmacokinetics of the Targeted Covalent Inhibitors Afatinib, Ibrutinib, and Neratinib , 2015, Drug Metabolism and Disposition.

[70]  Mitchell E Taub,et al.  Sex-, Species-, and Tissue-Specific Metabolism of Empagliflozin in Male Mouse Kidney Forms an Unstable Hemiacetal Metabolite (M466/2) That Degrades to 4-Hydroxycrotonaldehyde, a Reactive and Cytotoxic Species. , 2015, Chemical research in toxicology.

[71]  N. Hanioka,et al.  In vitro glucuronidation of propofol in microsomal fractions from human liver, intestine and kidney: tissue distribution and physiological role of UGT1A9. , 2014, Die Pharmazie.

[72]  G. S. Walker,et al.  Biosynthesis of Drug Metabolites and Quantitation Using NMR Spectroscopy for Use in Pharmacologic and Drug Metabolism Studies , 2014, Drug Metabolism and Disposition.

[73]  P. Ortiz de Montellano,et al.  Carbon-Carbon Bond Cleavage in Activation of the Prodrug Nabumetone , 2014, Drug Metabolism and Disposition.

[74]  Olivier Heudi,et al.  Biodistribution and Metabolism Studies of Lipid Nanoparticle–Formulated Internally [3H]-Labeled siRNA in Mice , 2014, Drug Metabolism and Disposition.

[75]  Y. Kalaidzidis,et al.  Image-based analysis of lipid nanoparticle–mediated siRNA delivery, intracellular trafficking and endosomal escape , 2013, Nature Biotechnology.

[76]  M. Nobilis,et al.  Analytical power of LLE-HPLC-PDA-MS/MS in drug metabolism studies: identification of new nabumetone metabolites. , 2013, Journal of pharmaceutical and biomedical analysis.

[77]  F. Natt,et al.  Metabolism Studies of Unformulated Internally [3H]-Labeled Short Interfering RNAs in Mice , 2013, Drug Metabolism and Disposition.

[78]  Christopher I. Jones,et al.  XRN 5'→3' exoribonucleases: structure, mechanisms and functions. , 2013, Biochimica et biophysica acta.

[79]  A. Kilcoyne,et al.  Absorption, distribution, metabolism, and excretion , 2013 .

[80]  R. Obach,et al.  Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy , 2013, Pharmacological Reviews.

[81]  C. Prakash,et al.  Radiolabeled mass-balance excretion and metabolism studies in laboratory animals: a commentary on why they are still necessary , 2013, Xenobiotica; the fate of foreign compounds in biological systems.

[82]  U. Argikar.  Unusual Glucuronides , 2012, Drug Metabolism and Disposition.

[83]  Jeffrey P. Jones,et al.  The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase , 2012, Drug Metabolism and Disposition.

[84]  A. Galetin,et al.  Drug–Drug Interaction Potential of Marketed Oncology Drugs: In Vitro Assessment of Time-Dependent Cytochrome P450 Inhibition, Reactive Metabolite Formation and Drug–Drug Interaction Prediction , 2012, Pharmaceutical Research.

[85]  L. Pustilnik,et al.  Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors. , 2011, Journal of medicinal chemistry.

[86]  Hannes G. Leisch,et al.  Baeyer-Villiger monooxygenases: more than just green chemistry. , 2011, Chemical reviews.

[87]  Y. Wong,et al.  A Baeyer-Villiger Oxidation Specifically Catalyzed by Human Flavin-Containing Monooxygenase 5 , 2011, Drug Metabolism and Disposition.

[88]  Deepak Dalvie,et al.  Aldehyde oxidase: an enzyme of emerging importance in drug discovery. , 2010, Journal of medicinal chemistry.

[89]  Kuresh Youdim,et al.  In Vitro-In Vivo Correlation for Intrinsic Clearance for Drugs Metabolized by Human Aldehyde Oxidase , 2010, Drug Metabolism and Disposition.

[90]  Chuang Lu,et al.  The Conduct of in Vitro Studies to Address Time-Dependent Inhibition of Drug-Metabolizing Enzymes: A Perspective of the Pharmaceutical Research and Manufacturers of America , 2009, Drug Metabolism and Disposition.

[91]  U. Hofmann,et al.  A Predominate Role of CYP1A2 for the Metabolism of Nabumetone to the Active Metabolite, 6-Methoxy-2-naphthylacetic Acid, in Human Liver Microsomes , 2009, Drug Metabolism and Disposition.

[92]  N. Penner,et al.  Human radiolabeled mass balance studies: objectives, utilities and limitations. , 2009, Biopharmaceutics & drug disposition.

[93]  I. MacRae,et al.  The RNA-induced Silencing Complex: A Versatile Gene-silencing Machine* , 2009, The Journal of Biological Chemistry.

[94]  Leonard Buckbinder,et al.  Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure-activity relationships and strategies for the elimination of reactive metabolite formation. , 2008, Bioorganic & medicinal chemistry letters.

[95]  J. Hochman,et al.  Metabolite identification of small interfering RNA duplex by high-resolution accurate mass spectrometry. , 2008, Rapid communications in mass spectrometry : RCM.

[96]  J. Wilusz,et al.  RNA recognition by 3'-to-5' exonucleases: the substrate perspective. , 2008, Biochimica et biophysica acta.

[97]  M. Bard,et al.  Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes. , 2007, Cell metabolism.

[98]  R. Obach,et al.  What is the Objective of the Mass Balance Study? A Retrospective Analysis of Data in Animal and Human Excretion Studies Employing Radiolabeled Drugs , 2007, Drug metabolism reviews.

[99]  K. Rentsch.  The importance of stereoselective determination of drugs in the clinical laboratory. , 2002, Journal of biochemical and biophysical methods.

[100]  F. Golley,et al.  Structure and Function , 2002, Science's STKE.

[101]  Y. Moriwaki,et al.  Widespread cellular distribution of aldehyde oxidase in human tissues found by immunohistochemistry staining. , 2001, Histology and histopathology.

[102]  S. Kitamura,et al.  The Role of Mammalian Intestinal Bacteria in the Reductive Metabolism of Zonisamide , 1997, The Journal of pharmacy and pharmacology.

[103]  J. Adams,et al.  Constitutive cyclooxygenase (COX‐1) and inducible cyclooxygenase (COX‐2): Rationale for selective inhibition and progress to date , 1996, Medicinal research reviews.

[104]  S Takeno,et al.  Involvement of the intestinal microflora in nitrazepam-induced teratogenicity in rats and its relationship to nitroreduction. , 1991, Teratology.

[105]  R. Haddock,et al.  Metabolism of nabumetone (BRL 14777) by various species including man. , 1984, Xenobiotica; the fate of foreign compounds in biological systems.

[106]  Cordula Stillhart,et al.  Addressing Today ’ s Absorption, Distribution, Metabolism, and Excretion (ADME) Challenges in the Translation of In Vitro ADME Characteristics to Humans: A Case Study of the SMN2 mRNA Splicing Modifier Risdiplam S , 2021 .

[107]  J. Miners,et al.  Enzyme kinetics of uridine diphosphate glucuronosyltransferases (UGTs). , 2014, Methods in molecular biology.

[108]  F. Guengerich,et al.  Cytochrome P-450 3A4: regulation and role in drug metabolism. , 1999, Annual review of pharmacology and toxicology.

[109]  T. Netscher,et al.  Design and development of chiral reagents for the chromatographic e.e. determination of chiral alcohols , 1996 .

[110]  G. Mannens,et al.  The metabolism and excretion of risperidone after oral administration in rats and dogs. , 1994, Drug metabolism and disposition: the biological fate of chemicals.

[111]  R. Remmel,et al.  Role of the intestinal microflora in clonazepam metabolism in the rat. , 1984, Xenobiotica; the fate of foreign compounds in biological systems.