In vitro to in vivo extrapolation of the complex drug-drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation.
Bupropion is a widely used antidepressant and smoking cessation aid and a strong inhibitor of CYP2D6 in vivo. Bupropion is administered as a racemic mixture of R- and S-bupropion and has stereoselective pharmacokinetics. Four primary metabolites of bupropion, threo- and erythro-hydrobupropion and R,R- and S,S-OH-bupropion, circulate at higher concentrations than the parent drug and are believed to contribute to the efficacy and side effects of bupropion as well as to the CYP2D6 inhibition. However, bupropion and its metabolites are only weak inhibitors of CYP2D6 in vitro, and the magnitude of the in vivo drug-drug interactions (DDI) caused by bupropion cannot be explained by the in vitro data even when CYP2D6 inhibition by the metabolites is accounted for. The aim of this study was to quantitatively explain the in vivo CYP2D6 DDI magnitude by in vitro DDI data. Bupropion and its metabolites were found to inhibit CYP2D6 stereoselectively with up to 10-fold difference in inhibition potency between enantiomers. However, the reversible inhibition or active uptake into hepatocytes did not explain the in vivo DDIs. In HepG2 cells and in plated human hepatocytes bupropion and its metabolites were found to significantly downregulate CYP2D6 mRNA in a concentration dependent manner. The in vivo DDI was quantitatively predicted by significant down-regulation of CYP2D6 mRNA and reversible inhibition of CYP2D6 by bupropion and its metabolites. This study is the first example of a clinical DDI resulting from CYP down-regulation and first demonstration of a CYP2D6 interaction resulting from transcriptional regulation.
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
Jennifer E
JE
Sager
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
Sasmita
S
Tripathy
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
Lauren S L
LS
Price
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, USA.
Abhinav
A
Nath
Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, WA, USA.
Justine
J
Chang
Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, WA, USA.
Alyssa
A
Stephenson-Famy
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA. Electronic address: ni2@uw.edu.
Nina
N
Isoherranen
D016642:Bupropion / Q000378:metabolism / Q000494:pharmacology*; D002853:Chromatography, Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D015536:Down-Regulation; D004347:Drug Interactions; D056945:Hep G2 Cells; D006801:Humans; D066298:In Vitro Techniques; D016540:Smoking Cessation; D053719:Tandem Mass Spectrometry
D016642:Bupropion; D019389:Cytochrome P-450 CYP2D6
Bupropion; CYP2D6; Drug-drug interactions; Enzyme regulation; In vitro to in vivo extrapolation