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SERTRALINE IS METABOLIZED BY MULTIPLE CYTOCHROME P450 ENZYMES, MONOAMINE OXIDASES, AND GLUCURONYL TRANSFERASES IN HUMAN: AN IN VITRO STUDY1. R. Scott Obach, 2. Loretta M. Cox and 3. Larry M. Tremaine + Author Affiliations 1. Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer, Inc., Groton, Connecticut 1. Address correspondence to: R. Scott Obach, MS 4088, Groton Laboratories, Pfizer, Inc., Groton, CT 06340. E-mail:

AbstractThe oxidative and conjugative metabolism of sertraline was examined in vitro to identify the enzymes involved in the generation of N-desmethyl, deaminated, and N-carbamoylglucuronidated metabolites in humans. In human liver microsomes, sertraline was Ndemethylated and deaminated by cytochrome P450 (P450) enzymes with overall Km values of 98 and 114 M, respectively, but the intrinsic clearance for N-demethylation was approximately 20fold greater than for deamination. Using P450 isoform-selective inhibitors and recombinant heterologously expressed enzymes, it was demonstrated that several P450 enzymes catalyzed sertraline N-demethylation, with CYP2B6 contributing the greatest extent, and lesser contributions from CYP2C19, CYP2C9, CYP3A4, and CYP2D6. For deamination, data supported a role for CYP3A4 and CYP2C19. Purified human monoamine oxidases A and B also catalyzed sertraline deamination with comparable Km values (230-270 M). Monoamine oxidase B catalyzed the reaction approximately 3-fold faster than did monoamine oxidase A. Sertraline N-carbamoyl glucuronidation was measured in human liver microsomes in bicarbonate buffer and under a CO2 atmosphere (Km = 50 M) and was catalyzed at the fastest rate by recombinant

human UGT2B7. The observation that multiple enzymes appear to be involved in sertraline metabolism suggests that there should be no single agent that could substantially alter the pharmacokinetics of sertraline, nor should there be any single drug-metabolizing enzyme genetic polymorphism (e.g., CYP2D6, CYP2C19, CYP2C9, UGT1A1) that could profoundly impact the pharmacokinetics of sertraline.


Article, publication date, and citation information can be found at doi:10.1124/dmd.104.002428. ABBREVIATIONS: P450, cytochrome P450; MAO, monoamine oxidase; PPP, 2phenyl-2-(1-piperdinyl)propane; RAF, relative activity factor; UDPGA, uridine diphosphoglucuronic acid; UGT, uridine diphosphoglucuronic acid transferase; HPLC, high-performance liquid chromatography; rP450, recombinant cytochrome P450; HLM, human liver microsome(s); CP-105,162, 4-(4-chlorophenyl)-1,2,3,4-tetrahydro-1naphthalenamine. o o

Received September 20, 2004. Accepted November 12, 2004.

The American Society for Pharmacology and Experimental Therapeutics

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Top 25 Psychiatric Medication Prescriptions for 2011

By John M. Grohol, Psy.D.

These are the top 25 psychiatric medications by number of U.S. prescriptions dispensed in 2011, according to IMS Health. Ive also provided their 2009 and 2005 ranking (you can view the 2009 list here). To put the percent changes below into perspective, the U.S. total population rose approximately 1.6 percent from 2009 to 2011. That suggests that anything above 1.6 percent change was driven by other factors more people seeking treatment, more pharmaceutical advertising and marketing, or some other factor. The biggest movers and shakers on the list were Celexa moving up 15 spots to grab the second most-prescribed psychiatric drug in 2011 and Wellbutrin XL, moving from 22 to 13. Drugs used to treat attention deficit hyperactivity disorder (ADHD) generic amphetamine salts and methylphenidate enjoyed big gains as well.

2011 2009 2005 Brand name Rank Rank Rank (generic name) 1. 2. 3. 4. 5. 6. 7. 1. 17. 4. 3. 5. 2. 6. 1. 11. 2. 5. 4. 3. NA Xanax (alprazolam) Celexa (citalopram) Zoloft (sertraline) Ativan (lorazepam) Prozac (fluoxetine HCL) Lexapro (escitalopram) Desyrel (trazodone HCL) Cymbalta (duloxetine) Valium (diazepam) Seroquel (quetiapine) Paxil (paroxetine HCL) Effexor XR (venlafaxine HCL ER) Wellbutrin XL (bupropion HCL XL) Risperdal (risperidone) Amphetamine salts (Generic) Abilify

Used for Anxiety Depression, Anxiety Depression, Anxiety, OCD, PTSD, PMDD Anxiety, panic disorder Depression, Anxiety Depression, Anxiety Depression, Anxiety Depression, Anxiety, fibromyalgia, diabetic neuropathy Anxiety, Panic disorder Bipolar disorder, Depression Depression, Anxiety, Panic disorder Depression, Anxiety, Panic disorder

U.S. Prescriptions (% change from 2009) 47,792,000 (9%) 37,728,000 (36%) 37,208,000 (8%) 27,172,000 (4%) 24,507,000 (6%) 23,707,000 (- 16%) 22,591,000 (15%) 17,770,000 (6%) 14,694,000 (6%) 14,213,000 (- 11%) 13,990,000 (- 6%) 12,469,000 (NA for HCL ER) 12,151,000 (77%) 12,092,000 (14%) 9,682,000 (36%) 8,881,000




9. 10. 11.

10. 8. 11.

9. 13. 10.







Depression Bipolar disorder, Schizophrenia, irritability in autism Attention deficit disorder Bipolar disorder,




15. 16.

11. 15.


(aripiprazole) 17. 19. NA Vyvanse (lisdexamfetamine) Wellbutrin SR (bupropion HCL SR) Vistaril* (hydroxyzine) Amphetamine salts ER (Generic) Buspar (buspirone) Zyprexa (olanzapine) Concerta (methylphenidate) Methylphenidate (generic) Pristiq (desvenlafaxine)

Schizophrenia, Depression Attention deficit disorder

(8%) 8,467,000 (50%) 8,456,000 (75%) 7,268,000 (9%) 6,499,000 (67%) 6,334,000 (15%) 4,576,000 (- 15%) 4,328,000 (- 45%) 4,248,000 (NA) 4,039,000 (61%)








Anxiety, tension




Attention deficit disorder

21. 22. 23. 24. 25.

18. 20. 16. NA 25.

19. 17. NA NA NA

Sleep, Anxiety Bipolar disorder, Schizophrenia Attention deficit disorder Attention deficit disorder Depression

Notes: If no percentage change is listed, we did not track it in 2005. NA Rank not available for this year. * This is not a psychiatric medication, but is often prescribed for a mental health issue.

How This Data is DerivedInformation in the National Prescription Audit (NPA) is derived from IMS Healths Xponent service, one of the most complete, national-level prescription databases in the U.S. Xponent captures roughly 70% Market Share of all prescriptions in the U.S. IMS then uses a patented projection methodology