von Moltke L L, Greenblatt D J, Court M H, Duan S X, Harmatz J S, Shader R I
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
J Clin Psychopharmacol. 1995 Apr;15(2):125-31. doi: 10.1097/00004714-199504000-00008.
In vitro preparations of human liver microsomes were used to study the inhibiting effects of two selective serotonin reuptake inhibitor (SSRI) antidepressants, paroxetine and fluvoxamine, on metabolism via hydroxylation of alprazolam and of desipramine. These reactions are mediated by Cytochromes P450-3A4 and P450-2D6, respectively. Paroxetine was a highly potent inhibitor of desipramine hydroxylation; the inhibition constant (Ki) value of 2.0 microM indicated greater inhibiting potency than fluoxetine or norfluoxetine. The in vitro data predicted in vivo impairment of desipramine clearance by coadministration of paroxetine which was in the same range as observed in a clinical study. Fluvoxamine, by contrast, was a much weaker inhibitor of desipramine hydroxylation, having a Ki value (16.6 microM) similar to those of sertraline and desmethylsertraline. For hydroxylation of alprazolam, paroxetine was a relatively weak inhibitor, approximately comparable to fluoxetine, whereas fluvoxamine showed inhibiting capacity similar to that of norfluoxetine. The in vitro data predicted the degree of impairment of alprazolam clearance observed in vitro model can therefore provide clinically relevant data on prediction of potential drug interactions with SSRIs.
利用人肝微粒体的体外制剂，研究了两种选择性5-羟色胺再摄取抑制剂（SSRI）抗抑郁药帕罗西汀和氟伏沙明对通过阿普唑仑和地昔帕明羟基化进行的代谢的抑制作用。这些反应分别由细胞色素P450 - 3A4和P450 - 2D6介导。帕罗西汀是地昔帕明羟基化的高效抑制剂；2.0微摩尔的抑制常数（Ki）值表明其抑制效力高于氟西汀或去甲氟西汀。体外数据预测，与帕罗西汀合用会导致地昔帕明清除率在体内受损，这与临床研究中观察到的情况处于同一范围。相比之下，氟伏沙明是地昔帕明羟基化的弱得多的抑制剂，其Ki值（16.6微摩尔）与舍曲林和去甲舍曲林的相似。对于阿普唑仑的羟基化，帕罗西汀是相对较弱的抑制剂，大致与氟西汀相当，而氟伏沙明显示出与去甲氟西汀相似的抑制能力。体外数据预测了阿普唑仑清除率受损的程度，体外模型因此可以提供关于预测与SSRI潜在药物相互作用的临床相关数据。
