Atypical antipsychotic metabolism and excretion.
BACKGROUND
The metabolic/biotransformation pathways of atypical antipsychotics (aripiprazole, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) have been characterized and reviewed. However, comparisons of excretory pathways remain unexplored.


OBJECTIVE
To analyze the excretion profile of atypical antipsychotic agents and compare the overall magnitude of metabolism (changed vs. unchanged drug) and route of excretion (feces vs. urine). Secondary objectives include providing: 1) dosing information in hepatic and renal impairment, and 2) context of the specific enzymes and pathways involved in each agents' biotransformation.


METHODS
Published literature and each manufacturer's radiolabeled drug absorption, distribution, metabolism and excretion data and U.S. prescribing information were reviewed.


RESULTS
With the exception of paliperidone, atypical antipsychotics undergo extensive metabolism (i.e., <or=50% of dose recovered unchanged). Quetiapine undergoes the greatest overall metabolism (<1% of the dose recovered unchanged) and paliperidone the least (59% recovered unchanged in the urine). Between-agent differences exist in the extent of cytochrome P450 (CYP450) metabolism and the specific isozymes involved. After administration of a radioactive dose, fecal elimination of unchanged drug plus metabolites ranged from 11% (paliperidone) to 71% (ziprasidone) and renal elimination ranged from 21% (ziprasidone) to 80% (paliperidone).


CONCLUSIONS
Understanding the differences in the elimination profiles of atypical antipsychotics agents may permit better-informed drug and dose selection in special populations such as those with comorbid conditions (e.g. hepatitis, diabetes, end-stage renal disease) or pharmacogenetic variability; or at risk for drug-drug interactions. The use of patient tailored drug and dose-selection may result in greater treatment efficacy and a reduction in adverse events.
Sheehan
J J
JJ
Ortho-McNeil Janssen Scientific Affairs, Titusville, New Jersey 08560-0200, USA. jsheeha2@its.jnj.com
Sliwa
J K
JK
Amatniek
J C
JC
Grinspan
A
A
Canuso
C M
CM
D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000627:therapeutic use / Q000652:urine; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D014150:Antipsychotic Agents; D003577:Cytochrome P-450 Enzyme System