Oganesian Aram, Shilling Adam D, Young-Sciame Ruth, Tran Judy, Watanyar Adiba, Azam Farooq, Kao John, Leung Louis
Incyte Corp, Wilmington, DE, USA.
Psychopharmacol Bull. 2009;42(2):47-63.
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.
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.
Desvenlafaxine and venlafaxine showed little or no reversible inhibition of various CYP enzymes (concentration that inhibits 50% [IC50] or inhibition constant [Ki] ~ or >100 muM). 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 muM) and did not act as substrates (efflux ratios <2) for efflux in Caco-2 monolayers.
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.
识别潜在的药代动力学药物相互作用是临床药物开发中的重要一步。我们基于去甲文拉法辛和文拉法辛对人细胞色素P450（CYP）和P-糖蛋白（P-gp）体外活性的抑制效力，评估并比较了它们的药物相互作用潜力。
在人肝微粒体中测定去甲文拉法辛和文拉法辛对CYP1A2、CYP2A6、CYP2C8、CYP2C9、CYP2C19、CYP2D6和CYP3A4的可逆抑制作用，以及对CYP2C9、CYP2C19、CYP2D6和CYP3A活性的基于机制的抑制作用。在Caco-2单层细胞中测定这些药物是否为P-gp的外排底物或抑制剂。
去甲文拉法辛和文拉法辛对各种CYP酶几乎没有或没有可逆抑制作用（抑制50%的浓度[IC50]或抑制常数[Ki]约为或>100μM）。此外，这两种药物都不作为CYP2C9、CYP2C19、CYP2D6或CYP3A的基于机制的抑制剂，因为在有或没有烟酰胺腺嘌呤二核苷酸磷酸再生系统预孵育的情况下，它们都没有降低这些酶中任何一种的IC50值。去甲文拉法辛和文拉法辛对P-gp活性的抑制作用很小（IC50值>250μM），并且在Caco-2单层细胞中不作为外排底物（外排比率<2）。
考虑到体外和现有的临床数据，去甲文拉法辛和文拉法辛通过抑制作为各种CYP酶底物的伴随药物的代谢清除，尤其是CYP2D6，似乎具有较低的药代动力学药物相互作用潜力。此外，这些数据表明去甲文拉法辛和文拉法辛与作为P-gp底物或抑制剂的伴随药物发生药代动力学相互作用的可能性很小。
