Altering metabolic profiles of drugs by precision deuteration: Reducing mechanism-based inhibition of CYP2D6 by Paroxetine

Journal of Pharmacology and Experimental Therapeutics

Volumn 354, Issue 1, 2015, Pages 43-54

  Uttamsingh, Vinita ^a   Gallegos, Richard ^a   Liu, Julie F ^a   Harbeson, Scott L ^a   Bridson, Gary W ^a   Cheng, Changfu ^a   Wells, David S ^a   Graham, Philip B ^a   Zelle, Robert ^a   Tung, Roger ^a  

^a Drug Metabolism and Pharmacokinetics   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 [(2,2 DIDEUTEROBENZO[D][1,3]DIOXOL 5 YLOXY)METHYL] 4 (4 FLUOROPHENYL)PIPERIDINE; CYTOCHROME P450 2D6; DEUTERIUM; DEXTROMETHORPHAN; PAROXETINE; PLACEBO; SEROTONIN RECEPTOR; SEROTONIN UPTAKE INHIBITOR; TAMOXIFEN; UNCLASSIFIED DRUG; CYTOCHROME P450 2D6 INHIBITOR;

ADULT; AGED; AREA UNDER THE CURVE; ARTICLE; CHEMICAL MODIFICATION; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG DOSE ESCALATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; ENZYME INACTIVATION; FEMALE; HUMAN; HUMAN CELL; HUMAN EXPERIMENT; IN VITRO STUDY; IN VIVO STUDY; LIVER MICROSOME; MAXIMUM PLASMA CONCENTRATION; NEUROTRANSMITTER UPTAKE; NONHUMAN; NORMAL HUMAN; PRECISION DEUTERATION; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RAT; SYNAPTOSOME; ANIMAL; BRAIN; CLINICAL TRIAL; DRUG INTERACTION; ISOTOPE LABELING; METABOLISM; PHASE 1 CLINICAL TRIAL; RADIOASSAY;

ANIMALS; BRAIN; CYTOCHROME P-450 CYP2D6; CYTOCHROME P-450 CYP2D6 INHIBITORS; DEUTERIUM; DOUBLE-BLIND METHOD; DRUG INTERACTIONS; FEMALE; HUMANS; ISOTOPE LABELING; MICROSOMES, LIVER; PAROXETINE; RADIOLIGAND ASSAY; RATS; RECEPTORS, SEROTONIN; SEROTONIN UPTAKE INHIBITORS; SYNAPTOSOMES; TAMOXIFEN;

EID: 84939440373     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.115.223768     Document Type: Article

References (32)

1. Alfaro CL, Lam YW, Simpson J, and Ereshefsky L (2000) CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intra-individual variability and plasma concentration correlations. J Clin Pharmacol 40: 58-66.
2. Bertelsen KM, Venkatakrishnan K, Von Moltke LL, Obach RS, and Greenblatt DJ (2003) Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab Dispos 31: 289-293.
3. Blagojevic N, Storr G, Allen JB, Hatanaka H, and Nakagawa H (1994) Treatment planning techniques for neutron capture therapy, in Proceedings of an international workshop on macro- and microdosimetry and treatment planning for neutron capture therapy, in Topics in Dosimetry & Treatment Planning for Neutron Capture Therapy (Zamenhof RG, Solares GR and Harling OK, eds); 1991 October 31-November 1; Massachusetts Institute of Technology. p 125, Advanced Medical Publishing, Inc., Madison, WI.
4. Bloomer JC, Woods FR, Haddock RE, Lennard MS, and Tucker GT (1992) The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes. Br J Clin Pharmacol 33:521-523.
5. Bordeleau L, Pritchard K, Goodwin P, and Loprinzi C (2007) Therapeutic options for the management of hot flashes in breast cancer survivors: an evidence-based review. Clin Ther 29:230-241.
6. Bourin M, Chue P, and Guillon Y (2001) Paroxetine: a review. CNS Drug Rev 7: 25-47.
7. Braman V, Graham P, Cheng C, Turnquist D, Harnett M, Sabounjian L, and Shipley J (2013) A randomized phase I evaluation of CTP-499, a novel deuterium-containing drug candidate for diabetic nephropathy. Clin Pharmacol Drug Dev 2: 53-66.
8. BrØsen K, Hansen JG, Nielsen KK, Sindrup SH, and Gram LF (1993) Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 44:349-355.
9. Deecher DC and Dorries K (2007) Understanding the pathophysiology of vasomotor symptoms (hot flushes and night sweats) that occur in perimenopause, menopause, and postmenopause life stages. Arch Women Ment Health 10:247-257.
10. Di Costanzo L, Moulin M, Haertlein M, Meilleur F, and Christianson DW (2007) Expression, purification, assay, and crystal structure of perdeuterated human arginase I. Arch Biochem Biophys 465:82-89.
11. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, et al. (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388.
12. Foster AB (1984) Deuterium isotope effects in studies of drug metabolism. Trends Pharmacol Sci 5:524-527.
13. Gant TG (2014) Using deuterium in drug discovery: leaving the label in the drug. J Med Chem 57:3595-3611.
14. Harbeson SL and Tung RD (2011) Deuterium in drug discovery and development. Annu Rep Med Chem 46:403-417.
15. Hertz DL, McLeod HL, and Irvin WJ, Jr (2012) Tamoxifen and CYP2D6: a contradiction of data. Oncologist 17:620-630.
16. Kaye CM, Haddock RE, Langley PF, Mellows G, Tasker TC, Zussman BD, and Greb WH (1989) A review of the metabolism and pharmacokinetics of paroxetine in man. Acta Psychiatr Scand Suppl 350:60-75.
17. Kitz R and Wilson IB (1962) Esters of methanesulfonic acid as irreversible inhibitors of acetylcholinesterase. J Biol Chem 237:3245-3249.
18. Kushner DJ, Baker A, and Dunstall TG (1999) Pharmacological uses and perspectives of heavy water and deuterated compounds. Can J Physiol Pharmacol 77: 79-88.
19. Lu XC, Shear DA, Graham PB, Bridson G, Uttamsingh V, Chen Z, Leung LY, and Tortella FC (2015) Dual therapeutic effects of C-10068, a dextromethorphan derivative, against post-traumatic nonconvulsive seizures and neuroinflammation in a rat model of penetrating ballistic-like brain injury. J Neurotrauma DOI: 10.1089/neu.2014.3766 [published ahead of print].
20. Marter WL, Hayes DW, and Jones DW (1982) Deuterium and tritium, in Encyclopedia of Chemical Processing and Design-Design of Experiments to Diffusion: Molecular (McKetta JC and Cunningham WA, eds) p 308, Marcel Dekker, Inc., New York, NY.
21. Mayhew BS, Jones DR, and Hall SD (2000) An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation. Drug Metab Dispos 28:1031-1037.
22. Murray M (2000) Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. Curr Drug Metab 1:67-84.
23. Nelson SD and Trager WF (2003) The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity. Drug Metab Dispos 31: 1481-1498.
24. Obach RS, Baxter JG, Liston TE, Silber BM, Jones BC, MacIntyre F, Rance DJ, and Wastall P (1997) The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Ther 283:46-58.
25. Orr ST, Ripp SL, Ballard TE, Henderson JL, Scott DO, Obach RS, Sun H, and Kalgutkar AS (2012) Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure-activity relationships and discovery strategies to mitigate drug-drug interaction risks. J Med Chem 55:4896-4933.
26. Paxil (2012) Package insert. GlaxoSmithKline, Research Triangle Park, NC.
27. Schmid B, Bircher J, Preisig R, and Küpfer A (1985) Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther 38:618-624.
28. Shao L and Hewitt MC (2010) The kinetic isotope effect in the search for deuterated drugs. Drug News Perspect 23:398-404.
29. Silverman RB (1995) Mechanism-based enzyme inactivators. Methods Enzymol 249: 240-283.
30. Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, and Flockhart DA (2003) Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758-1764.
31. Stearns V, Slack R, Greep N, Henry-Tilman R, Osborne M, Bunnell C, Ullmer L, Gallagher A, Cullen J, Gehan E, et al. (2005) Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol 23:6919-6930.
32. Wiberg KB (1955) The deuterium isotope effect. Chem Rev 55:713-743.