Desvenlafaxine and Venlafaxine Exert Minimal In Vitro Inhibition of Human Cytochrome P450 and P-Glycoprotein Activities

Objective: Identification of potential pharmacokinetic drug-drug interactions is an important step in clinical drug development. We assessed and compared the drug-drug interaction potential of desvenlafaxine and venlafaxine, based on their inhibitory potency on human cytochrome P450 (CYP) and P-glycoprotein (P-gp) activities in vitro. Methods: Reversible inhibition of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and mechanism-based inhibition of CYP2C9, CYP2C19, CYP2D6, and CYP3A activity by desvenlafaxine and venlafaxine were determined in human liver microsomes. Whether these drugs were substrates for efflux or inhibitors of P-gp were determined in Caco-2 monolayers. Results: Desvenlafaxine and venlafaxine showed little or no reversible inhibition of various CYP enzymes (concentration that inhibits 50% [IC50] or inhibition constant [Ki] ~ or >100 μM). In addition, neither drug acted as a mechanism-based inhibitor of CYP2C9, CYP2C19, CYP2D6, or CYP3A as they did not reduce the IC50 value for any of these enzymes in the presence of preincubations with or without a nicotinamide adenine dinucleotide phosphate-regenerating system. Desvenlafaxine and venlafaxine showed little inhibition of P-gp activity (IC50 values >250 μM) and did not act as substrates (efflux ratios <2) for efflux in Caco-2 monolayers. Conclusions: Considering in vitro and available clinical data, desvenlafaxine and venlafaxine appear to have low potential for pharmacokinetic drug-drug interactions via inhibiting the metabolic clearance of concomitant drugs that are substrates of various CYP enzymes, in particular CYP2D6. In addition, these data suggest that desvenlafaxine and venlafaxine exhibit little potential for pharmacokinetic interactions with concomitant drugs that are substrates or inhibitors of P-gp. Psychopharmacology Bulletin. 2009;42(2):47–63.