Enhancing the Properties of Natural Products and Other Drugs: Deuterium: A Novel Approach
Authors
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Dr APJ Abdul Kalam Research Laboratory, Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur – 603203, Tamil Nadu ,IN
M. Koushika -
Dr APJ Abdul Kalam Research Laboratory, Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur – 603203, Tamil Nadu ,ING. V. Anjana
DOI:
https://doi.org/10.18311/jnr/2024/35570Keywords:
Deuterium, Kinetic Isotopic Effect, Metabolism, Natural CompoundAbstract
Deuterium substitution is a new approach used to enhance the metabolic profile of a drug. The carbon-deuterium bond seems to be stronger than a usual carbon-hydrogen bond. It leads to improved biological half-life and prolonged action of the drug. The deuterated drugs also show improved pharmacokinetics of the drug and reduce the dosing frequency. This paves the way for drugs from natural sources with good therapeutic effects but poor pharmacokinetic profiles, which can be deuterated for improved properties. Though this seems to be an alternate pathway, the isotope exchange with hydrogen has to be studied well for toxicity and the safety profile of the drug should be evaluated. The present review provides an outline of the deuterium approach in natural products and other drugs which are opted for deuterium to improve the metabolic profile.
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Copyright (c) 2024 M. Koushika, G. V. Anjana (Author)
This work is licensed under a Creative Commons Attribution 4.0 International License.
Accepted 2024-01-12
Published 2024-03-01
References
Veljkovic V, Veljkovic N, Este JA, Huther A, Dietrich U. Application of the EIIP/ISM bioinformatics concept in development of new drugs. Current Medicinal Chemistry. 2007; 14(4):441-53. https://doi.org/10.2174/092986707779941014 PMid:17305545.
Meanwell NA. Synopsis of some recent tactical application of bioisosteres in drug design. Journal of Medicinal Chemistry. 2011; 54(8):2529-91. https://doi.org/10.1021/jm1013693 PMid:21413808.
Gant TG. Using deuterium in drug discovery: leaving the label in the drug. Journal of Medicinal Chemistry. 2014; 57(9):3595-611. https://doi.org/10.1021/jm4007998 PMid:24294889.
Mouli HC, Vinod A, Kumari S, Tiwari AK, Kathiravan MK, Peraman R. Deuterated driven new chemical entities: An optimistic way to improve therapeutic efficacy. Bioorganic Chemistry. 2023. p. 106490. https://doi.org/10.1016/j.bioorg.2023.106490
Buteau KC. Deuterated drugs: unexpectedly nonobvious. J High Tech. L. 2009; 10:22.
Bell RP. Liversidge lecture. Recent advances in the study of kinetic hydrogen isotope effects. Chemical Society Reviews. 1974; 3(4):513-44. https://doi.org/10.1039/cs9740300513
Guengerich FP. Kinetic deuterium isotope effects in cytochrome P450 oxidation reactions. Journal of Labelled Compounds and Radiopharmaceuticals. 2013; 56(9-10):428-31. https://doi.org/10.1002/jlcr.3031 PMid:24285515 PMCid: PMC4861049.
Panda N, Zakki Uddin SK, Anjana GV, Ramalingam P, Palaniappan S, Mohan Maruga Raja MK, Kathiravan MK. Deuterium - A natural isotope to combat microbial resistance. In Journal of Natural Remedies. 2023; 23(2).
Pirali T, Serafini M, Cargnin S, Genazzani AA. Applications of deuterium in medicinal chemistry. Journal of Medicinal Chemistry. 2019; 62(11):5276-97. https://doi.org/10.1021/acs.jmedchem.8b01808 PMid:30640460.
Hok L, Mavri J, Vianello R. The effect of deuteration on the H2 receptor histamine binding profile: a computational insight into modified hydrogen bonding interactions. Molecules. 2020; 25(24):6017. https://doi.org/10.3390/molecules25246017 PMid:33353215 PMCid: PMC7766521.
Kashyap D, Tuli HS, Yerer MB, Sharma A, Sak K, Srivastava S, Pandey A, Garg VK, Sethi G, Bishayee A. Natural productbased nanoformulations for cancer therapy: Opportunities and challenges. In Seminars in Cancer Biology. 2021; 69:5-23. https://doi.org/10.1016/j.semcancer.2019.08.014 PMid:31421264.
Siviero A, Gallo E, Maggini V, Gori L, Mugelli A, Firenzuoli F, Vannacci A. Curcumin, a golden spice with a low bioavailability. Journal of Herbal Medicine. 2015; 5(2):57-70. https://doi.org/10.1016/j.hermed.2015.03.001
Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: Lessons learned from clinical trials. The AAPS Journal. 2013; 15:195-218. https://doi.org/10.1208/s12248-012-9432-8 PMid:23143785 PMCid: PMC3535097.
Stanić Z. Curcumin, a compound from natural sources, a true scientific challenge-A review. Plant Foods for Human Nutrition. 2017; 72:1-12. https://doi.org/10.1007/s11130-016-0590-1 PMid:27995378.
Talib WH, Alsalahat I, Daoud S, Abutayeh RF, Mahmod AI. Plant-derived natural products in cancer research: Extraction, mechanism of action, and drug formulation. Molecules. 2020; 25(22):5319. https://doi.org/10.3390/molecules25225319 PMid:33202681 PMCid: PMC7696819.
Dhyani P, Quispe C, Sharma E, Bahukhandi A, Sati P, Attri DC, Szopa A, Sharifi-Rad J, Docea AO, Mardare I, Calina D. Anticancer potential of alkaloids: a key emphasis to colchicine, vinblastine, vincristine, vindesine, vinorelbine and vincamine. Cancer Cell International. 2022; 22(1):1-20. https://doi.org/10.1186/s12935-022-02624-9 PMid:35655306 PMCid: PMC9161525.
Zhao Y, Pan H, Liu W, Liu E, Pang Y, Gao H, He Q, Liao W, Yao Y, Zeng J, Guo J. Menthol: An underestimated anticancer agent. Frontiers in Pharmacology. 2023; 14:1148790. https://doi.org/10.3389/fphar.2023.1148790 PMid:37007039 PMCid: PMC10063798.
Garcia-Oliveira P, Otero P, Pereira AG, Chamorro F, Carpena M, Echave J, Fraga-Corral M, Simal-Gandara J, Prieto MA. Status and challenges of plant-anticancer compounds in cancer treatment. Pharmaceuticals. 2021; 14(2):157. https://doi.org/10.3390/ph14020157 PMid:33673021 PMCid: PMC7918405.
Dutta S, Mahalanobish S, Saha S, Ghosh S, Sil PC. Natural products: An upcoming therapeutic approach to cancer. Food and Chemical Toxicology. 2019; 128:240-55. https://doi.org/10.1016/j.fct.2019.04.012 PMid:30991130.
Belete TM. Recent updates on the development of deuterium-containing drugs for the treatment of cancer. Drug Design, Development and Therapy. 2022; 16:3465-72. https://doi.org/10.2147/DDDT.S379496 PMid:36217450 PMCid: PMC9547620.
Anjana GV, Kathiravan MK. Antimicrobial activity of curcumin and deuterated curcumin. JNR [Internet]. 2022; 22(3):424-31. https://doi.org/10.18311/jnr/2022/29686
Girgis S, Lee LR. Treatment of dry age‐related macular degeneration: A review. Clinical Exper Ophthalmology [Internet]. 2023; 51(8):835-52. https://doi.org/10.1111/ceo.14294 PMid:37737509.
Miller JF, Andrews CW, Brieger M, Furfine ES, Hale MR, Hanlon MH, Hazen RJ, Kaldor I, McLean EW, Reynolds D, Sammond DM. Ultra-potent P1 modified arylsulfonamide HIV protease inhibitors: The discovery of GW0385. Bioorganic and Medicinal Chemistry Letters. 2006; 16(7):1788-94. https://doi.org/10.1016/j.bmcl.2006.01.035 PMid:16458505.
Hazen R, Harvey R, Ferris R, Craig C, Yates P, Griffin P, Miller J, Kaldor I, Ray J, Samano V, Furfine E. In vitro antiviral activity of the novel, tyrosyl-based Human Immunodeficiency Virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV. Antimicrobial Agents and Chemotherapy. 2007; 51(9):3147-54. https://doi.org/10.1128/AAC.00401-07 PMid:17620375 PMCid: PMC2043237.
Mutlib AE. Application of stable isotope-labeled compounds in metabolism and in metabolism-mediated toxicity studies. Chemical Research in Toxicology. 2008; 21(9):1672-89. https://doi.org/10.1021/tx800139z PMid:18702535.
Velthuisen EJ, Baughman TM, Johns BA, Temelkoff DP, Weatherhead JG. Synthesis and pharmacokinetic profile of highly deuterated brecanavir analogues. European Journal of Medicinal Chemistry. 2013; 63:202-12. https://doi.org/10.1016/j.ejmech.2013.02.001 PMid:23474906.
Savi P, Herbert JM. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. In Seminars in Thrombosis and Hemostasis. 2005; 31(2):174-83. https://doi.org/10.1055/s-2005-869523 PMid:15852221.
Savi P, Herbert JM, Pflieger AM, Dol F, Delebassee D, Combalbert J, Defreyn G, Maffrand JP. Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel. Biochemical Pharmacology. 1992; 44(3):527-32. https://doi.org/10.1016/0006-2952(92)90445-O PMid:1510701.
Savi P, Combalbert J, Gaich C, Rouchon MC, Maffrand JP, Berger Y, Herbert JM. The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A. Thrombosis and Haemostasis. 1994;72(08):313-7. https://doi.org/10.1055/s-0038-1648859 PMid:7831671.
Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM. Identification and biological activity of the active metabolite of clopidogrel. Thrombosis and Haemostasis. 2000; 84(5):891-6. https://doi.org/10.1055/s-0037-1614133 PMid:11127873.
Pereillo JM, Maftouh M, Andrieu A, Uzabiaga MF, Fedeli O, Savi P, Pascal M, Herbert JM, Maffrand JP, Picard C. Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metabolism and Disposition. 2002; 30(11):1288-95. https://doi.org/10.1124/dmd.30.11.1288 PMid:12386137.
Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metabolism and Disposition. 2010; 38(1):92-9. https://doi.org/10.1124/dmd.109.029132 PMid:19812348.
Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. New England Journal of Medicine. 2009; 360(4):354-62. https://doi.org/10.1056/NEJMoa0809171 PMid:19106084.
Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: A meta-analysis. Jama. 2010; 304(16):1821-30. https://doi.org/10.1001/jama.2010.1543 PMid:20978260 PMCid: PMC3048820.
Xu X, Zhao X, Yang Z, Wang H, Meng X, Su C, Liu M, Fawcett JP, Yang Y, Gu J. Significant improvement of metabolic characteristics and bioactivities of clopidogrel and analogues by selective deuteration. Molecules. 2016; 21(6):704. https://doi.org/10.3390/molecules21060704 PMid:27248988 PMCid: PMC6274316.
Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T. Development of a secondgeneration antiandrogen for treatment of advanced prostate cancer. Science. 2009; 324(5928):787-90. https://doi.org/10.1126/science.1168175 PMid:19359544 PMCid: PMC2981508.
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, De Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ. Increased survival with enzalutamide in prostate cancer after chemotherapy. New England Journal of Medicine. 2012; 367(13):1187-97. https://doi.org/10.1056/NEJMoa1207506 PMid:22894553.
Ning YM, Pierce W, Maher VE, Karuri S, Tang SH, Chiu HJ, Palmby T, Zirkelbach JF, Marathe D, Mehrotra N, Liu Q. Enzalutamide for treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel: US Food and Drug Administration drug approval summary. Clinical Cancer Research. 2013; 19(22):6067-73. https://doi.org/10.1158/1078-0432.CCR-13-1763 PMid:24141628.
Jiang J, Pang X, Li L, Dai X, Diao X, Chen X, Zhong D, Wang Y, Chen Y. Effect of N-methyl deuteration on metabolism and pharmacokinetics of enzalutamide. Drug Design, Development and Therapy. 2016; 10:2181-91. https://doi.org/10.2147/DDDT.S111352 PMid:27462143 PMCid: PMC4939996.
Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A. ARN-509: A novel antiandrogen for prostate cancer treatment. Cancer Research. 2012; 72(6):1494-503. https://doi.org/10.1158/0008-5472.CAN-11-3948 PMid:22266222 PMCid: PMC3306502.
Jung ME, Ouk S, Yoo D, Sawyers CL, Chen C, Tran C, Wongvipat J. Structure-activity relationship for thiohydantoin androgen receptor antagonists for Castration-Resistant Prostate Cancer (CRPC). Journal of Medicinal Chemistry. 2010; 53(7):2779-96. https://doi.org/10.1021/jm901488g PMid:20218717 PMCid: PMC3180999.
Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009; 324(5928):787-90. https://doi.org/10.1126/science.1168175 PMid:19359544 PMCid: PMC2981508.
Pang X, Wang Y, Chen Y. Design, synthesis, and biological evaluation of deuterated apalutamide with improved pharmacokinetic profiles. Bioorganic and Medicinal Chemistry Letters. 2017; 27(12):2803-6. https://doi.org/10.1016/j.bmcl.2017.04.071 PMid:28478926.
LoRusso PM, Rudin CM, Borad MJ, Vernillet L, Darbonne WC, Mackey H, DiMartino JF, De Sauvage F, Low JA, Von Hoff DD. A first-in-human, first-in-class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumours. Journal of Clinical Oncology. 2008; 26(15_suppl):3516. https://doi.org/10.1200/jco.2008.26.15_suppl.3516
Geeraert P, Williams JS, Brownell I. Targeting the hedgehog pathway to treat basal cell carcinoma. Journal of Drugs in Dermatology: JDD. 2013; 12(5):519-23.
Robarge KD, Brunton SA, Castanedo GM, Cui Y, Dina MS, Goldsmith R, Gould SE, Guichert O, Gunzner JL, Halladay J, Jia W. GDC-0449-A potent inhibitor of the hedgehog pathway. Bioorganic and Medicinal Chemistry Letters. 2009; 19(19):5576-81. https://doi.org/10.1016/j.bmcl.2009.08.049 PMid:19716296.
Wong H, Chen JZ, Chou B, Halladay JS, Kenny JR, La H, Marsters Jr JC, Plise E, Rudewicz PJ, Robarge K, Shin Y. Preclinical assessment of the absorption, distribution, metabolism and excretion of GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl) phenyl)-4-(methylsulfonyl) benzamide), an orally bioavailable systemic hedgehog signalling pathway inhibitor. Xenobiotica. 2009; 39(11):850-61. https://doi.org/10.3109/00498250903180289 PMid:19845436.
Wong H, Theil FP, Cui Y, Marsters JC, Khojasteh SC, Vernillet L, La H, Song X, Wang H, Morinello EJ, Deng Y. Interplay of dissolution, solubility, and nonsink permeation determines the oral absorption of the hedgehog pathway inhibitor GDC-0449 in dogs: An investigation using preclinical studies and physiologically based pharmacokinetic modelling. Drug Metabolism and Disposition. 2010; 38(7):1029-38. https://doi.org/10.1124/dmd.110.032680 PMid: 20406853.
Wang F, Jiang H, Deng Y, Yu J, Zhan M, Zhao L, Chen Y. Design, synthesis and biological evaluation of deuterated Vismodegib for improving pharmacokinetic properties. Bioorganic and Medicinal Chemistry Letters. 2018; 28(14):2399-402. https://doi.org/10.1016/j.bmcl.2018.06.025 PMid: 29929879.
Kowanetz M, Ferrara N. Vascular endothelial growth factor signalling pathways: therapeutic perspective. Clinical Cancer Research. 2006; 12(17):5018-22. https://doi.org/10.1158/1078-0432.CCR-06-1520 PMid: 16951216.
Nakamura K, Taguchi E, Miura T, Yamamoto A, Takahashi K, Bichat F, Guilbaud N, Hasegawa K, Kubo K, Fujiwara Y, Suzuki R. KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Research. 2006; 66(18):9134-42. https://doi.org/10.1158/0008-5472.CAN-05-4290 PMid:16982756.
Taguchi E, Nakamura K, Miura T, Shibuya M, Isoe T. Anti‐tumor activity and tumour vessel normalisation by the vascular endothelial growth factor receptor tyrosine kinase inhibitor KRN951 in a rat peritoneal disseminated tumour model. Cancer Science. 2008 ; 99(3):623-30. https://doi.org/10.1111/j.1349-7006.2007.00724.x PMid: 18201272.
Berge EM, Bowles DW, Flaig TW, Lam ET, Jimeno A. Tivozanib: Practical implications for renal cell carcinoma and other solid tumours. Drugs of Today (Barcelona, Spain: 1998). 2013; 49(5):303-15. https://doi.org/10.1358/dot.2013.49.5.1960218 PMid: 23724410.
Guo S, Pang X, Peng L, Zhan M, Fan L, Gong Y, Kang F, Chen Y. Design, synthesis and biological evaluation of deuterated Tivozanib for improving pharmacokinetic properties. Bioorganic and Medicinal Chemistry Letters. 2015; 25(11):2425-8. https://doi.org/10.1016/j.bmcl.2015.03.088 PMid: 25908516.
Raffa RB, Friderichs EL, Reimann WO, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. Journal of Pharmacology and Experimental Therapeutics. 1992; 260(1):275-85. PMid: 1309873.
Shao L, Abolin C, Hewitt MC, Koch P, Varney M. Derivatives of tramadol for increased duration of effect. Bioorganic and Medicinal Chemistry Letters. 2006; 16(3):691-4. https://doi.org/10.1016/j.bmcl.2005.10.024 PMid:16257206.
Crofford LJ. COX-1 and COX-2 tissue expression: Implications and predictions. The Journal of Rheumatology. Supplement. 1997; 49:15-9.
Hawkey CJ. COX-2 inhibitors. The Lancet. 1999; 353(9149):307-14. https://doi.org/10.1016/S0140-6736(98)12154-2 PMid:9929039.
Schneider F, Hillgenberg M, Koytchev R, Alken RG. Enhanced plasma concentration by selective deuteration of rofecoxib in rats. Arzneimittelforschung. 2006; 56(04):295-300. https://doi.org/10.1055/s-0031-1296724 PMid:16724516.
World Health Organization. The selection and use of essential medicines: Report of the WHO expert committee, 2017 (including the 20th WHO model list of essential medicines and the 6th model list of essential medicines for children). World Health Organization. 2017.
Usach I, Melis V, Peris JE. Non‐nucleoside reverse transcriptase inhibitors: A review on pharmacokinetics, pharmacodynamics, safety and tolerability. Journal of the International AIDS Society. 2013; 16(1):18567. https://doi.org/10.7448/IAS.16.1.18567 PMid:24008177 PMCid: PMC3764307.
Pollard RB, Robinson P, Dransfield K. Safety profile of nevirapine, a nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus infection. Clinical Therapeutics. 1998; 20(6):1071-92. https://doi.org/10.1016/S0149-2918(98)80105-7 PMid:9916603.
Zhang C, Wang W, Zhou M, Han Y, Xie J, Qiu Z, Guo F, Li Y, Wang H, Ghanem KG, Li T. The interaction of CD4 T-cell count and nevirapine hepatotoxicity in China: A change in national treatment guidelines may be warranted. Journal of Acquired Immune Deficiency Syndromes Journal of Acquired Immune Deficiency Syndromes. 2013; 62(5):540-5. https://doi.org/10.1097/QAI.0b013e3182845cc7 PMid:23288032.
Sharma AM, Klarskov K, Uetrecht J. Nevirapine bioactivation and covalent binding in the skin. Chemical Research in Toxicology. 2013; 26(3):410-21. https://doi.org/10.1021/tx3004938 PMid:23387501.
Chen J, Mannargudi BM, Xu L, Uetrecht J. Demonstration of the metabolic pathway responsible for nevirapine-induced skin rash. Chemical Research in Toxicology. 2008; 21(9):1862-70. https://doi.org/10.1021/tx800177k PMid:18729332.
Sharma AM, Li Y, Novalen M, Hayes MA, Uetrecht J. Bioactivation of nevirapine to a reactive quinone methide: implications for liver injury. Chemical Research in Toxicology. 2012; 25(8):1708-19. https://doi.org/10.1021/tx300172s PMid:22793666 PMCid: PMC3475366.
Huebert ND, Palfreyman MG, Haegele KD. A comparison of the effects of reversible and irreversible inhibitors of aromatic L-amino acid decarboxylase on the half-life and other pharmacokinetic parameters of oral L-3, 4-dihydroxyphenylalanine. Drug Metabolism and Disposition. 1983; 11(3):195-200.
Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of Parkinson’s disease (2009). Neurology. 2009; 72(21 Supplement 4):S1-36. https://doi.org/10.1212/WNL.0b013e3181a1d44c
Salat D, Tolosa E. Levodopa in the treatment of Parkinson’s disease: Current status and new developments. Journal of Parkinson’s disease. 2013; 3(3):255-69. https://doi.org/10.3233/JPD-130186 PMid:23948989.
Wiberg KB. The deuterium isotope effect. Chemical Reviews. 1955; 55(4):713-43. https://doi.org/10.1021/cr50004a004
Schneider F, Erisson L, Beygi H, Bradbury M, Cohen‐ Barak O, Grachev ID, Guzy S, Loupe PS, Levi M, McDonald M, Savola JM. Pharmacokinetics, metabolism and safety of deuterated L‐DOPA (SD‐1077)/carbidopa compared to L‐DOPA/carbidopa following single oral dose administration in healthy subjects. British Journal of Clinical Pharmacology. 2018; 84(10):2422-32. https://doi.org/10.1111/bcp.13702 PMid:29959802 PMCid: PMC6138493.
Trunzer M, Faller B, Zimmerlin A. Metabolic soft spot identification and compound optimization in early discovery phases using metasite and LC-MS/MS validation. Journal of Medicinal Chemistry. 2009; 52(2):329-35. https://doi.org/10.1021/jm8008663 PMid:19108654.
De Voss JJ, Sibbesen O, Zhang Z, Ortiz de Montellano PR. Substrate docking algorithms and prediction of the substrate specificity of cytochrome P450cam and its L244A mutant. Journal of the American Chemical Society. 1997; 119(24):5489-98. https://doi.org/10.1021/ja970349v
Zhang Z, Sibbesen O, Johnson RA, De Montellano PR. The substrate specificity of cytochrome P450cam. Bioorganic and Medicinal Chemistry. 1998; 6(9):1501-8. https://doi.org/10.1016/S0968-0896(98)00091-1 PMid:9801821.
Gallant JE, Deresinski S. Tenofovir disoproxil fumarate. Clinical Infectious Diseases. 2003; 37(7):944-50. https://doi.org/10.1086/378068 PMid:13130407.
Venkatakrishnan K, Greenblatt DJ, Von Moltke LL, Schmider J, Harmatz JS, Shader RI. Five distinct human cytochromes mediate amitriptyline N‐demethylation in vitro: Dominance of CYP 2C19 and 3A4. The Journal of Clinical Pharmacology. 1998; 38(2):112-21. https://doi.org/10.1002/j.1552-4604.1998.tb04399.x PMid:9549641.
Ulrich S, Läuter J. Comprehensive survey of the relationship between serum concentration and therapeutic effect of amitriptyline in depression. Clinical Pharmacokinetics. 2002; 41:853-76. https://doi.org/10.2165/00003088-200241110-00004 PMid:12190332.
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