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

Abstract

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 erythrohydrobupropion 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.

Does In Vitro Cytochrome P450 Downregulation Translate to In Vivo Drug‐Drug Interactions? Preclinical and Clinical Studies With 13‐cis‐Retinoic Acid

“…Recent studies have suggested that in vitro CYP downregulation by small molecules translates to clinical DDIs, 4,18,22 but the data on IVIVE of CYP downregulation are controversial. The data obtained here show that concurrent downregulation of CYP2D6 mRNA and induction of CYP3A4 in human hepatocytes in the absence of cytotoxicity does not unequivocally translate to in vivo DDIs.…”

“…The overall effect of the three compounds on CYP expression in vivo was predicted assuming that all three precipitants (13cisRA, atRA, and 4-oxo-13cisRA) bind to the same receptor to result in altered CYP expression via a competitive mechanism, as described previously. 18 The prediction for the change in exposure of the sensitive CYP2D6 probe substrate dextromethorphan following dosing of 13cisRA to steady state was performed as previously described 19 with an adaptation to account for the presence of m number of retinoids k each competing for binding to the receptor of interest:…”

Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib

“…Investigators have reported downregulation of CYP450 gene expression, [29][30][31][32][33][34][35] some of which may be clinically relevant. For example, CYP2C9 downregulation has been observed in microarray analysis of human hepatocytes treated with A-792611 (10 µM, 48-hour treatments), a human immunodeficiency virus protease inhibitor and antagonist of the pregnane X receptor.…”

Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive Control

“…Transcriptional downregulation of P450s by chemicals was identified as an area requiring further exploration more than 10 years ago (Riddick et al, 2004). Despite this finding, published observations of druginduced downregulation by small molecules in vitro are scarce (Healan-Greenberg et al, 2008;Krausova et al, 2011;Yang et al, 2014;Zamek-Gliszczynski et al, 2014;Sager et al, 2017). Whereas potential mechanisms for downregulation have been identified (as detailed later herein), none has established a clinical effect for the major inducible enzymes (CYP1A2, CYP2B6, CYP2C, or CYP3A) from these in vitro observations.…”