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Drug Metabolism Reviews Volume 54, 2022 - Issue 3
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Review Articles

Biotransformation novel advances – 2021 year in review

S. Cyrus Khojasteha Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, CA, USACorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0002-8385-9288
ORCID Icon,
Upendra A. Argikarb Non-clinical Development, Bill and Melinda Gates Medical Research Institute, Cambridge, MA, USAORCID Iconhttps://orcid.org/0000-0002-0939-0813
ORCID Icon,
Sungjoon Choa Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, CA, USAORCID Iconhttps://orcid.org/0000-0003-1215-9759
ORCID Icon,
Rachel Crouchc Department of Pharmaceutical Sciences, Lipscomb University College of Pharmacy and Health Sciences, Nashville, TN, USAORCID Iconhttps://orcid.org/0000-0002-4525-6072
ORCID Icon,
Carley J. S. Heckd Medicine Design, Pfizer Worldwide Research, Development and Medical, Groton, CT, USAORCID Iconhttps://orcid.org/0000-0002-6842-3670
ORCID Icon,
Kevin M. Johnsona Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, CA, USAORCID Iconhttps://orcid.org/0000-0003-0479-4242
ORCID Icon,
Amit S. Kalgutkare Medicine Design, Pfizer Worldwide Research, Development and Medical, Cambridge, MA, USAORCID Iconhttps://orcid.org/0000-0001-9701-756X
ORCID Icon,
Lloyd Kingf Quantitative Drug Discovery, UCB Biopharma UK, Slough, UKORCID Iconhttps://orcid.org/0000-0002-3301-7533
ORCID Icon,
Hlaing (Holly) Mawg Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USAORCID Iconhttps://orcid.org/0000-0002-4051-7958
ORCID Icon,
Herana Kamal Seneviratneh Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USAORCID Iconhttps://orcid.org/0000-0002-7221-7060
ORCID Icon,
Shuai Wanga Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, CA, USAORCID Iconhttps://orcid.org/0000-0002-3282-1343
ORCID Icon,
Cong Weii Drug Metabolism and Pharmacokinetics, Biogen Inc, Cambridge, MA, USAORCID Iconhttps://orcid.org/0000-0003-2310-9255
ORCID Icon,
Donglu Zhanga Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, CA, USA
&
Klarissa D. Jacksonj Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USAORCID Iconhttps://orcid.org/0000-0002-9388-9800
ORCID Icon show all
Pages 207-245 | Received 03 May 2022, Accepted 29 Jun 2022, Published online: 30 Aug 2022

References

  • Baillie TA, Dalvie D, Rietjens IMCM, Khojasteh SC. 2016. Biotransformation and bioactivation reactions – 2015 literature highlights. Drug Metab Rev. 48(2):113–138.
  • Khojasteh SC, Argikar UA, Driscoll JP, Heck CJS, King L, Jackson KD, Jian W, Kalgutkar AS, Miller GP, Kramlinger V, et al. 2021. Novel advances in biotransformation and bioactivation research – 2020 year in review. Drug Metab Rev. 53(3):384–433.
  • Khojasteh SC, Bumpus NN, Driscoll JP, Miller GP, Mitra K, Rietjens IMCM, Zhang D. 2019. Biotransformation and bioactivation reactions – 2018 literature highlights. Drug Metab Rev. 51(2):121–161.
  • Khojasteh SC, Driscoll JP, Jackson KD, Miller GP, Mitra K, Rietjens IMCM, Zhang D. 2020. Novel advances in biotransformation and bioactivation research-2019 year in review. Drug Metab Rev. 52(3):333–365.
  • Khojasteh SC, Miller GP, Mitra K, Rietjens IMCM. 2018. Biotransformation and bioactivation reactions – 2017 literature highlights. Drug Metab Rev. 50(3):221–255.
  • Khojasteh SC, Rietjens IMCM, Dalvie D, Miller G. 2017. Biotransformation and bioactivation reactions – 2016 literature highlights. Drug Metab Rev. 49(3):285–317.
  • Kramlinger VM, Dalvie D, Heck CJS, Kalgutkar AS, O'Neill J, Su D, Teitelbaum AM, Totah RA. 2022. Future of biotransformation science in the pharmaceutical industry. Drug Metab Dispos. 50:258–267.

References

  • Penner N, Klunk LJ, Prakash C. 2009. Human radiolabeled mass balance studies: objectives, utilities and limitations. Biopharm Drug Dispos. 30:185–203.
  • Pillai G, Chibale K, Constable EC, Keller AN, Gutierrez MM, Mirza F, Sengstag C, Masimirembwa C, Denti P, Maartens G, et al. 2018. The Next Generation Scientist program: capacity-building for future scientific leaders in low- and middle-income countries. BMC Med Educ. 18(1):233.
  • Stepan AF, Karki K, McDonald WS, Dorff PH, Dutra JK, Dirico KJ, Won A, Subramanyam C, Efremov IV, O’Donnell CJ, et al. 2011. Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as c-secretase inhibitors. J Med Chem. 54(22):7772–7783.
  • Taub ME, Ludwig-Schwellinger E, Ishiguro N, Kishimoto W, Yu H, Wagner K, Tweedie D. 2015. 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. Chem Res Toxicol. 28(1):103–115.
  • Walker DP, Bi FC, Kalgutkar AS, Bauman JN, Zhao SX, Soglia JR, Aspnes GE, Kung DW, Klug-McLeod J, Zawistoski MP, et al. 2008. Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure-activity relationships and strategies for the elimination of reactive metabolite formation. Bioorg Med Chem Lett. 18(23):6071–6077.
  • Walker GS, Bauman JN, Ryder TF, Smith EB, Spracklin DK, Obach RS. 2014. Biosynthesis of drug metabolites and quantitation using NMR spectroscopy for use in pharmacologic and drug metabolism studies. Drug Metab Dispos. 42:1627–1639.
  • White RE, Evans DC, Hop CE, Moore DJ, Prakash C, Surapaneni S, Tse FL. 2013. Radiolabeled mass-balance excretion and metabolism studies in laboratory animals: a commentary on why they are still necessary. Xenobiotica. 43:219–225, discussion 226–227.

References

  • Agarwal S, Simon AR, Goel V, Habtemariam BA, Clausen VA, Kim JB, Robbie GJ. 2020. Pharmacokinetics and pharmacodynamics of the small interfering ribonucleic acid, givosiran, in patients with acute hepatic porphyria. Clin Pharmacol Ther. 108(1):63–72.
  • Chong S, Agarwal S, Agarwal S, Aluri KC, Arciprete M, Brown C, Charisse K, Cichocki J, Fitzgerald K, Goel V, et al. 2021. The nonclinical disposition and PK/PD properties of GalNAc-conjugated siRNA are highly predictable and build confidence in translation to man. Drug Metab Dispos. DOI:10.1124/dmd.121.000428.
  • Committee for Medicinal Products for Human Use (CHMP), EMA. 2020. Givisoran Assessment report (EMA/CHMP/70703/2020). https://www.ema.europa.eu/en/documents/assessment-report/givlaari-epar-public-assessment-report_en.pdf.
  • Nair JK, Attarwala H, Sehgal A, Wang Q, Aluri K, Zhang X, Gao M, Liu J, Indrakanti R, Schofield S, et al. 2017. Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc–siRNA conjugates. Nucleic Acids Res. 45(19):10969–10977.
  • Ramsden D, Wu JT, Zerler B, Iqbal S, Jiang J, Clausen V, Aluri K, Gu Y, Dennin S, Kim J, et al. 2019. In vitro drug-drug interaction evaluation of GalNAc conjugated siRNAs against CYP450 enzymes and transporters. Drug Metab Dispos. 47(10):1183–1194.

References

  • Agarwal S, Simon AR, Goel V, Habtemariam BA, Clausen VA, Kim JB, Robbie GJ. 2020. Pharmacokinetics and pharmacodynamics of the small interfering ribonucleic acid (siRNA), givosiran, in patients with acute hepatic porphyria. Clin Pharmacol Ther. 1:63–72.
  • Center for Drug Evaluation and Research (CDER) Food and Drug Administration. Multi-discipline review: Givosiran. NDA 212194. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212194Orig1s000MultidisciplineR.pdf.
  • Chakraborty C, Sharma AR, Sharma G, Doss CGP, Lee SS. 2017. Therapeutic miRNA and siRNA: moving from bench to clinic as next generation medicine. Mol Ther Nucleic Acids. 8:132–143.
  • Christensen J, Litherland K, Faller T, van de Kerkhof E, Natt F, Hunziker J, Krauser J, Swart P. 2013. Metabolism studies of unformulated internally [3H]-labeled short interfering RNAs in mice. Drug Metab Dispos. 41(6):1211–1219.
  • Christensen J, Litherland K, Faller T, van de Kerkhof E, Natt F, Hunziker J, Boos J, Beuvink I, Bowman K, Baryza J, et al. 2014. Biodistribution and metabolism studies of lipid nanoparticle formulated internally [3H]-labeled siRNA in mice. Drug Metab Dispos. 42(3):431–440.
  • Gilleron J, Querbes W, Zeigerer A, Borodovsky A, Marsico G, Schubert U, Manygoats K, Seifert S, Andree C, Stoter M, et al. 2013. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat Biotechnol. 31(7):638–646.
  • Humphreys SC, Thayer MB, Campbell J, Chen WLK, Adams D, Lade JM, Rock BM. 2020. Emerging siRNA design principles and consequences for biotransformation and disposition in drug development. J Med Chem. 63(12):6407–6422.
  • Husser C, Brink A, Zell M, Muller MB, Koller E, Schadt S. 2017. Identification of GalNAc-conjugated antisense oligonucleotide metabolites using an untargeted and generic approach based on high resolution mass spectrometry. Anal Chem. 89(12):6821–6826.
  • Ibrahim H, Wilusz J, Wilusz CJ. 2008. RNA recognition by 3’-to-5’ exonucleases: the substrate perspective. Biochim. Biophys. Acta, Gene Regul. Mech. 1779(4):256–265.
  • Johannes L, Lucchino M. 2018. Current challenges in delivery and cytosolic translocation of therapeutic RNAs. Nucleic Acid Ther. 28(3):178–193.
  • Lennox KA, Behlke MA. 2016. Cellular localization of long noncoding RNAs affects silencing by RNAi more than by antisense oligonucleotides. Nucleic Acids Res. 44(2):863–877.
  • Nagarajan VK, Jones CI, Newbury SF, Green PJ. 2013. XRN 5’→3’ exoribonucleases: structure, mechanisms, and functions. Biochim Biophys Acta Gene Regul Mech. 1829(6–7):590–603.
  • Pratt AJ, MacRae IJ. 2009. The RNA-induced silencing complex: a versatile gene-silencing machine. J Biol Chem. 284(27):17897–17901.
  • Shemesh CS, Yu RZ, Gaus HJ, Greenlee S, Post N, Schmidt K, Migawa MT, Seth PP, Zanardi TA, Prakash TP, et al. 2016. Elucidation of the biotransformation pathways of a GalNAc3-conjugated antisense oligonucleotide in rats and monkeys. Mol Ther Nucleic Acids. 5(5):e319.
  • Thayer MB, Lade JM, Doherty D, Xie F, Basiri B, Barnaby OS, Bala NS, Rock BM. 2019. Application of locked nucleic acid oligonucleotides for siRNA preclinical bioanalytics. Sci Rep. 9(1):3566.
  • Wittrup A, Ai A, Liu X, Hamar P, Trifonova R, Charisse K, Manoharan M, Kirchhausen T, Lieberman J. 2015. Visualizing lipidformulated siRNA release from endosomes and target gene knockdown. Nat Biotechnol. 33(8):870–876.
  • Wittrup A, Lieberman J. 2015. Knocking down disease: a progress report on siRNA therapeutics. Nat Rev Genet. 16(9):543–552.
  • Zou Y, Tiller P, Chen IW, Beverly M, Hochman J. 2008. Metabolite identification of small interfering RNA duplex by high-resolution accurate mass spectrometry. Rapid Commun Mass Spectrom. 22(12):1871–1881.

References

  • Abbasi A, Paragas EM, Joswig-Jones CA, Rodgers JT, Jones JP. 2019. Time course of aldehyde oxidase and why it is nonlinear. Drug Metab Dispos. 47(5):473–483.
  • Basit A, Neradugomma NK, Wolford C, Fan PW, Murray B, Takahashi RH, Khojasteh SC, Smith BJ, Heyward S, Totah RA, et al. 2020. Characterization of differential tissue abundance of major non-CYP enzymes in human. Mol Pharm. 17(11):4114–4124.
  • Hartmann T, Terao M, Garattini E, Teutloff C, Alfaro JF, Jones JP, Leimkühler S. 2012. The impact of single nucleotide polymorphisms on human aldehyde oxidase. Drug Metab Dispos. 40(5):856–864.
  • Kozminski KD, Selimkhanov J, Heyward S, Zientek MA. 2021. Contribution of extrahepatic aldehyde oxidase activity to human clearance. Drug Metab Dispos. 49(9):743–749.
  • Manevski N, King L, Pitt WR, Lecomte F, Toselli F. 2019. Metabolism by aldehyde oxidase: drug design and complementary approaches to challenges in drug discovery. J Med Chem. 62(24):10955–10994.
  • Zientek M, Jiang Y, Youdim K, Obach RS. 2010. In vitro-in vivo correlation for intrinsic clearance for durgs metabolized by human aldehyde oxidase. Drug Metab Dispos. 38(8):1322–1327.

References

  • Dick RA. 2018. Refinement of in vitro methods for identification of aldehyde oxidase substrates reveals metabolites of kinase inhibitors. Drug Metab Dispos. 46(6):846–859.
  • Glaenzel U, Jin Y, Hansen R, Schroer K, Rahmanzadeh G, Pfaar U, Jaap van Lier J, Borell H, Meissner A, Camenisch G, et al. 2020. Absorption, distribution, metabolism, and excretion of capmatinib (INC280) in healthy male volunteers and in vitro aldehyde oxidase phenotyping of the major metabolite. Drug Metab Dispos. 48(10):873–885.
  • Kozminski KD, Selimkhanov J, Heyward S, Zientek MA. 2021. Contribution of extrahepatic aldehyde oxidase activity to human clearance. Drug Metab Dispos. 49(9):743–749.
  • Kücükgöze G, Terao M, Garattini E, Leimkühler S. 2017. Direct comparison of the enzymatic characteristics and superoxide production of the four aldehyde oxidase enzymes present in mouse. Drug Metab Dispos. 45(8):947–955.
  • Moriwaki Y, Yamamoto T, Takahashi S, Tsutsumi Z, Hada T. 2001. Widespread cellular distribution of aldehyde oxidase in human tissues found by immunohistochemistry staining. Histol Histopathol. 16(3):745–753.
  • Terao M, Romao MJ, Leimkuhler S, Bolis M, Fratelli M, Coelho C, Santos-Silva T, Garattini E. 2016. Structure and function of mammalian aldehyde oxidases. Arch Toxicol. 90(4):753–780.

References

  • Eng H, Tseng E, Cerny MA, Goosen TC, Obach RS. 2020. Cytochrome P450 3A time-dependent inhibition assays are too sensitive for identification of drug causing clinically significant drug-drug interactions: a comparison of human liver microsomes and hepatocytes and definition of boundaries for inactivation rate constants. Drug Metab Dispos. 49(6):442–450.
  • Grimm SW, Einolf HJ, Hall SD, He K, Lim HK, Ling KH, Lu C, Nomeir AA, Seibert E, Skordos KW, et al. 2009. 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. Drug Metab Dispos. 37(7):1355–1370.
  • Guengerich FP. 1999. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol. 39:1–17.
  • Kenny JR, Mukadam S, Zhang C, Tay S, Collins C, Galetin A, Khojasteh SC. 2012. 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. Pharm Res. 29(7):1960–1976.
  • Tseng E, Eng H, Lin J, Cerny MA, Tess DA, Goosen TC, Obach RS. 2021. Static and dynamic projections of drug-drug interactions caused by cytochrome P450 3A time-dependent inhibitors measured in human liver microsomes and hepatocytes. Drug Metab Dispos. 49(10):947–960.

References

  • Ghanem CI, Pérez MJ, Manautou JE, Mottino AD. 2016. Acetaminophen from liver to brain: new insights into drug pharmacological action and toxicity. Pharmacol Res. 109:119–131.
  • Heslop JA, Rowe C, Walsh J, Sison-Young R, Jenkins R, Kamalian L, Kia R, Hay D, Jones RP, Malik HZ, et al. 2017. Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile. Arch Toxicol. 91(1):439–452.
  • Hughes AL, Powell DW, Bard M, Eckstein J, Barbuch R, Link AJ, Espenshade PJ. 2007. Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes. Cell Metab. 5(2):143–149.
  • Jee A, Sernoskie SC, Uetrecht J. 2021. Idiosyncratic drug-induced liver injury: mechanistic and clinical challenges. IJMS. 22(6):2954.
  • Kwon D, Kim SM, Correia MA. 2020. Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications. Acta Pharm Sin B. 10(1):42–60.
  • Lauschke VM, Shafagh RZ, Hendriks DFG, Ingelman-Sundberg M. 2019. 3D primary hepatocyte culture systems for analyses of liver diseases, drug metabolism, and toxicity: emerging culture paradigms and applications. Biotechnol J. 14(7):e1800347.
  • McGuire MR, Mukhopadhyay D, Myers SL, Mosher EP, Brookheart RT, Kammers K, Sehgal A, Selen ES, Wolfgang MJ, Bumpus NN, et al. 2021. Progesterone receptor membrane component 1 (PGRMC1) binds and stabilizes cytochromes P450 through a heme-independent mechanism. J Biol Chem. 297(5):101316.
  • Waring RH. 2020. Cytochrome P450: genotype to phenotype. Xenobiotica. 50(1):9–18.

References

  • Baranello G, Darras BT, Day JW, Deconinck N, Klein A, Masson R, Mercuri E, Rose K, El-Khairi M, Gerber M, et al. 2021. Risdiplam in type 1 spinal muscular atrophy. N Engl J Med. 384(10):915–923.
  • Fowler S, Brink A, Cleary Y, Guenther A, Heinig K, Husser C, Kletzl H, Kratochwil NA, Mueller L, Savage M, et al. 2021. Addressing today’s ADME challenges in the translation of in vitro absorption, distribution, metabolism and excretion characteristics to human: a case study of the SMN2 mRNA splicing modifier risdiplam. Drug Metab Dispos. 50(1):65–75.
  • Kletzl H, Marquet A, Günther A, Tang W, Heuberger J, Groeneveld GJ, Birkhoff W, Mercuri E, Lochmüller H, Wood C, et al. 2019. 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. Neuromuscul Disord. 29(1):21–29. DDIs
  • Ratni H, Ebeling M, Baird J, Bendels S, Bylund J, Chen KS, Denk N, Feng Z, Green L, Guerard M, et al. 2018. Discovery of risdiplam, a selective survival of motor neuron-2 (SMN2) gene splicing modifier for the treatment of spinal muscular atrophy (SMA). J Med Chem. 61(15):6501–6517.
  • Roberts MS, Magnusson BM, Burczynski FJ, Weiss M. 2002. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet. 41(10):751–790.
  • Sturm S, Günther A, Jaber B, Jordan P, Al Kotbi N, Parkar N, Cleary Y, Frances N, Bergauer T, Heinig K, et al. 2019. A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier. Br J Clin Pharmacol. 85(1):181–193.

References

  • Griswold DE, Adams JL. 1996. Constitutive cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-2): rationale for selective inhibition and progress to date. Med Res Rev. 16(2):181–206.
  • Haddock RE, Jeffery DJ, Lloyd JA, Thawley AR. 1984. Metabolism of nabumetone (BRL 14777) by various species including man. Xenobiotica. 14(4):327–337.
  • Lai WG, Farah N, Moniz GA, Wong N. 2011. A Baeyer-Villiger oxidation specifically catalyzed by human flavin-containing monooxygenase 5. Drug Metab Dispos. 39(1):61–70.
  • Leisch H, Morley K, Lau PC. 2011. Baeyer-Villiger Monooxygenases: more than just green chemistry. Chem Rev. 111(7):4165–4222.
  • Matsumoto K, Hasegawa T, Ohara K, Kamei T, Koyanagi J, Akimoto M. 2021. Role of human flavin-containing monooxygenase (FMO) 5 in the metabolism of nabumetone: Baeyer-Villiger oxidation in the activation of the intermediate metabolite, 3-hydroxynabumetone, to the active metabolite, 6-methoxy-2-naphthylacetic acid in vitro. Xenobiotica. 51(2):155–166.
  • Matsumoto K, Hasegawa T, Ohara K, Takei C, Kamei T, Koyanagi J, Takahashi T, Akimoto M. 2020. A metabolic pathway for the prodrug nabumetone to the pharmacologically active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA) by non-cytochrome P450 enzymes. Xenobiotica. 50(7):783–792.
  • Nobilis M, Mikušek J, Szotáková B, Jirásko R, Holčapek M, Chamseddin C, Jira T, Kučera R, Kuneš J, Pour M. 2013. Analytical power of LLE-HPLC-PDA-MS/MS in drug metabolism studies: identification of new nabumetone metabolites. J Pharm Biomed Anal. 80:164–172.
  • Obach RS. 2013. Pharmacologically active drug metabolites: impact on drug discovery and pharmacotherapy. Pharmacol Rev. 65(2):578–640.
  • Turpeinen M, Hofmann U, Klein K, Mürdter T, Schwab M, Zanger UM. 2009. A predominate role of CYP1A2 for the metabolism of nabumetone to the active metabolite, 6-methoxy-2-naphthylacetic acid, in human liver microsomes. Drug Metab Dispos. 37(5):1017–1024.
  • Varfaj F, Zulkifli SNA, Park HG, Challinor VL, De Voss JJ, Ortiz de Montellano PR. 2014. Carbon-carbon bond cleavage in activation of the prodrug nabumetone. Drug Metab Dispos. 42(5):828–838.

References

  • Asano D, Hamaue S, Zahir H, Shiozawa H, Nishiya Y, Kimura T, Kazui M, Yamamura N, Ikeguchi M, Shibayama T, et al. 2022. CYP2C8-mediated formation of a human disproportionate metabolite of the selective Na(V)1.7 inhibitor DS-1971a, a mixed cytochrome P450 and aldehyde oxidase substrate. Drug Metab Dispos. 50(3):235–242.
  • Asano D, Shibayama T, Shiozawa H, Inoue SI, Shinozuka T, Murata S, Watanabe N, Yoshinari K. 2021. Evaluation of species difference in the metabolism of the selective Na(V)1.7 inhibitor DS-1971a, a mixed substrate of cytochrome P450 and aldehyde oxidase. Xenobiotica. 51(9):1060–1070.
  • Ballard TE, Kratochwil N, Cox LM, Moen MA, Klammers F, Ekiciler A, Goetschi A, Walter I. 2020. Simplifying the execution of hepatopac metID experiments: metabolite profile and intrinsic clearance comparisons. Drug Metab Dispos. 48(9):804–810.
  • Fowler S, Brink A, Cleary Y, Günther A, Heinig K, Husser C, Kletzl H, Kratochwil N, Mueller L, Savage M, et al. 2022. 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. Drug Metab Dispos. 50(1):65–75.
  • Kamel A, Bowlin S, Hosea N, Arkilo D, Laurenza A. 2021. 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. Drug Metab Dispos. 49(2):121–132.
  • Pryde DC, Dalvie D, Hu Q, Jones P, Obach RS, Tran TD. 2010. Aldehyde oxidase: an enzyme of emerging importance in drug discovery. J Med Chem. 53(24):8441–8460.
  • Schadt S, Bister B, Chowdhury SK, Funk C, Hop CECA, Humphreys WG, Igarashi F, James AD, Kagan M, Khojasteh SC, et al. 2018. A decade in the MIST: learnings from investigations of drug metabolites in drug development under the “metabolites in safety testing” regulatory guidance. Drug Metab Dispos. 46(6):865–878.
  • Sharma R, Litchfield J, Atkinson K, Eng H, Amin NB, Denney WS, Pettersen JC, Goosen TC, Di L, Lee E, et al. 2014. Metabolites in safety testing assessment in early development: a case study with a glucokinase activator. Drug Metab Dispos. 42(11):1926–1939.
  • Shinozuka T, Kobayashi H, Suzuki S, Tanaka K, Karanjule N, Hayashi N, Tsuda T, Tokumaru E, Inoue M, Ueda K, et al. 2020. Discovery of DS-1971a, a potent, selective NaV1.7 inhibitor. J Med Chem. 63:10204–10220.
  • Surapaneni S, Yerramilli U, Bai A, Dalvie D, Brooks J, Wang X, Selkirk JV, Yan YG, Zhang P, Hargreaves R, et al. 2021. Absorption, metabolism, and excretion, in vitro pharmacology, and clinical pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor modulator. Drug Metab Dispos. 49(5):405–419.

References

  • Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ. 2015. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 5:12007.
  • Sugawara T, Baumgart SJ, Nevedomskaya E, Reichert K, Steuber H, Lejeune P, Mumberg D, Haendler B. 2019. Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models. Int J Cancer. 145(5):1382–1394.
  • Rentsch KM. 2002. The importance of stereoselective determination of drugs in the clinical laboratory. J Biochem Biophys Methods. 54(1–3):1–9.
  • Walther W, Netscher T. 1996. Design and development of chiral reagents for the chromatographic determination of chiral alcohols. Chirality. 8(5):397–401.
  • Katzung BG. 2004. The nature of drugs. In: Basic and clinical pharmacology. 9th ed. New York: Lange Medical Books/McGraw Hill; p. 3–5.
  • U.S. Food and Drug Administration (FDA). 1992. Guidance for development of new stereoisomeric drugs. Center for drug evaluation and research. US department of health and human services, Rockville, MD.
  • European Medicines Agency (EMA). 1993. Investigation of chiral active substances. European Medicines Agency, London.

References

  • Badman MK, Chen J, Desai S, Vaidya S, Neelakantham S, Zhang J, Gan L, Danis K, Laffitte B, Klickstein LB.,. 2020. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel non-bile acid FXR agonist tropifexor (LJN452) in healthy volunteers. Clin Pharmacol Drug Dev. 9(3):395–410.
  • Hernandez ED, Zheng L, Kim Y, Fang B, Liu B, Valdez RA, Dietrich WF, Rucker PV, Chianelli D, Schmeits J, et al. 2019. Tropifexor-mediated abrogation of steatohepatitis and fibrosis is associated with the antioxidative gene expression profile in rodents. Hepatol Commun. 3(8):1085–1097.
  • Polyzos SA, Kountouras J, Mantzoros CS. 2020. Obeticholic acid for the treatment of nonalcoholic steatohepatitis: expectations and concerns. Metabolism. 104:154144.
  • Tully DC, Rucker PV, Chianelli D, Williams J, Vidal A, Alper PB, Mutnick D, Bursulaya B, Schmeits J, Wu X, et al. 2017. Discovery of tropifexor (LJN452), a highly potent non-bile acid FXR agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). J Med Chem. 60(24):9960–9973.

References

  • Rood JJM, Jamalpoor A, van Hoppe S, van Haren MJ, Wasmann RE, Janssen MJ, Schinkel AH, Masereeuw R, Beijnen JH, Sparidans RW. 2021. Extrahepatic metabolism of ibrutinib. Invest New Drugs. 39(1):1–14.
  • Shibata Y, Chiba M. 2015. The role of extrahepatic metabolism in the pharmacokinetics of the targeted covalent inhibitors afatinib, ibrutinib, and neratinib. Drug Metab Dispos. 43(3):375–384.

References

  • Surapaneni S, Yerramilli U, Bai A, Dalvie D, Brooks J, Wang X, Selkirk JV, Yan YG, Zhang P, Hargreaves R, et al. 2021. Absorption, metabolism, and excretion, in vitro pharmacology, and clinical pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor modulator. Drug Metab Dispos. 49(5):405–419.
  • Tran JQ, Zhang P, Ghosh A, Liu L, Syto M, Wang X, Palmisano M. 2020. Single-dose pharmacokinetics of ozanimod and its major active metabolites alone and in combination with gemfibrozil, itraconazole, or rifampin in healthy subjects: a randomized, parallel-group, open-label study. Adv Ther. 37(10):4381–4395.
  • Tran JQ, Zhang P, Walker S, Ghosh A, Syto M, Wang X, Harris S, Palmisano M. 2020. Multiple-dose pharmacokinetics of ozanimod and its major active metabolites and the pharmacodynamic and pharmacokinetic interactions with pseudoephedrine, a sympathomimetic agent, in healthy subjects. Adv Ther. 37(12):4944–4958.

References

  • Bai A, Shanmugasundaram V, Selkirk JV, Surapaneni S, Dalvie D. 2021. 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. Drug Metab Dispos. 49(8):601–609.
  • Elmer GW, Remmel RP. 1984. Role of the intestinal microflora in clonazepam metabolism in the rat. Xenobiotica. 14(11):829–840.
  • Kitamura S, Sugihara K, Kuwasako M, Tatsumi K. 1997. The role of mammalian intestinal bacteria in the reductive metabolism of zonisamide. J Pharm Pharmacol. 49(3):253–256.
  • Meuldermans W, Hendrickx J, Mannens G, Lavrijsen K, Janssen C, Bracke J, Le Jeune L, Lauwers W, Heykants J. 1994. The metabolism and excretion of risperidone after oral administration in rats and dogs. Drug Metab Dispos. 22:129–138.
  • O’Donnell MP, Fox BW, Chao P-H, Schroeder FC, Sengupta P. 2020. A neurotransmitter produced by gut bacteria modulates host sensory behaviour. Nature. 583(7816):415–420.
  • Roffey SJ, Obach RS, Gedge JI, Smith DA. 2007. What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabeled drugs. Drug Metab Rev. 39(1):17–43.
  • Surapaneni S, Yerramilli U, Bai A, Dalvie D, Brooks J, Wang X, Selkirk JV, Yan YG, Zhang P, Hargreaves R, et al. 2021. Absorption, metabolism, and excretion, in vitro pharmacology, and clinical pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor modulator. Drug Metab Dispos. 49(5):405–419.
  • Takeno S, Sakai T. 1991. Involvement of the intestinal microflora in nitrazepam-induced teratogenicity in rats and its relationship to nitroreduction. Teratology. 44(2):209–214.
  • van de Steeg E, Schuren FHJ, Obach RS, van Woudenbergh C, Walker GS, Heerikhuisen M, Nooijen IHG, Vaes WHJ. 2018. An ex vivo fermentation screening platform to study drug metabolism by human gut microbiota. Drug Metab Dispos. 46(11):1596–1607.
  • van Kessel SP, Frye AK, El-Gendy AO, Castejon M, Keshavarzian A, van Dijk G, El Aidy S. 2019. Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease. Nat Commun. 10(1):310.
  • Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL. 2019. Separating host and microbiome contributions to drug pharmacokinetics and toxicity. Science. 363(6427):aat9931.

References

  • Argikar UA. 2012. Unusual glucuronides. Drug Metab Dispos. 40(7):1239–1251.
  • Foti RS, Argikar UA. 2019. UDP-glucuronosyltransferases (UGTs). In: Handbook of drug metabolism. 3rd ed. Boca Raton: CRC Press; p. 109–159.
  • Gunduz M, Cirello AL, Klimko P, Dumouchel JL, Argikar UA. 2017. 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. Drug Metab Lett. 11(2):144–148.
  • Mukai M, Isobe T, Okada K, Murata M, Shigeyama M, Hanioka N. 2015. Species and sex differences in propofol glucuronidation in liver microsomes of humans, monkeys, rats and mice. Pharmazie. 70(7):466–470.
  • Mukai M, Tanaka S, Yamamoto K, Murata M, Okada K, Isobe T, Shigeyama M, Hichiya H, Hanioka N. 2014. In vitro glucuronidation of propofol in microsomal fractions from human liver, intestine and kidney: tissue distribution and physiological role of UGT1A9. Pharmazie. 69(11):829–832.
  • Wang-Lakshman L, Mendonza AE, Huber R, Walles M, He Y, Jarugula V. 2021. Pharmacokinetics, metabolism, and excretion of licogliflozin, a dual inhibitor of SGLT1/2, in rats, dogs, and humans. Xenobiotica. 51(4):413–426.
  • Zhou J, Argikar UA, Miners JO. 2021. Enzyme Kinetics of Uridine Diphosphate Glucuronosyltransferases (UGTs). Methods Mol Biol. 2342:301–338.

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