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PI‐35
Author(s) -
Wang J. S.,
Zhu H. J.,
Gibson B. B.,
Donovan J. L.,
Markowitz J. S.,
DeVane L. C.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.056
Subject(s) - bupropion , sertraline , pharmacology , metabolite , chemistry , p glycoprotein , active metabolite , drug , reuptake inhibitor , antidepressant , medicine , biochemistry , serotonin , receptor , pathology , smoking cessation , multiple drug resistance , hippocampus , antibiotics
BACKGROUND The ABCB1 drug transporter P‐glycoprotein (P‐gp) plays an important function in the blood‐brain barrier limiting a broad spectrum of substrates from entering the central nervous system. In the present study, the transport activity of P‐gp for sertraline, bupropion, and their major metabolites was studied using an ATPase assay in expressed human P‐gp membranes. METHODS Sertraline, desmethylsertraline, bupropion and its three major metabolites, threo‐amino alcohol (TB), erythro‐amino alcohol (EB), and hydroxy metabolite (HB) were studied for their ability to stimulate inorganic P i in expressed human P‐gp membranes as a marker for the binding affinity for P‐gp. Verapamil was included as a positive control. The classical Michaelis‐Menten equation was used for characterizing the kinetic data. RESULTS Sertraline and desmethylsertraline had high affinity for P‐gp. The V max /K m values of sertraline (1.6) and desmethylsertraline (1.4) were comparable with that of verapamil (1.7). Bupropion and its three metabolites showed very weak affinity for P‐gp. Their V max /K m values were generally lower than 0.01. CONCLUSION The results of the present study indicate that sertraline and desmethylsertraline are actively transported by P‐gp, whereas bupropion and its three major metabolites TB, EB, and HB are not substrates of P‐gp. These findings help to explain observations of drug‐drug interactions with these antidepressants and the high inter‐patient variability in drug disposition. Clinical Pharmacology & Therapeutics (2005) 79 , P16–P16; doi: 10.1016/j.clpt.2005.12.056