Voorman R L, Maio S M, Hauer M J, Sanders P E, Payne N A, Ackland M J
Drug Metabolism Research, Pharmacia and Upjohn, Kalamazoo, MI 49007, USA.
Drug Metab Dispos. 1998 Jul;26(7):631-9.
The metabolism of delavirdine was examined using liver microsomes from several species with the aim of comparing metabolite formation among species and characterizing the enzymes responsible for delavirdine metabolism. Incubation of 10 microM [14C]delavirdine with either an S9 fraction from human jejunum or liver microsomes from rat, human, dog, or monkey followed by high pressure liquid chromatography analysis showed qualitatively similar metabolite profiles among species with the formation of three significant metabolites. The major metabolite was desalkyl delavirdine; however, the identity of MET-7 and MET-7a (defined by high pressure liquid chromatography elution) could not be unambiguously established, but they seem to be related pyridine hydroxy metabolites, most likely derived from 6'-hydroxylation of the pyridine ring. The apparent KM for delavirdine desalkylation activity ranged from 4.4 to 12.6 microM for human, rat, monkey, and dog microsomes, whereas Vmax ranged from 0.07 to 0.60 nmol/min/mg protein, resulting in a wide range of intrinsic clearance (6-135 microL/min/mg protein). Delavirdine desalkylation by microsomes pooled from several human livers was characterized by a KM of 6.8 +/- 0.8 microM and Vmax of 0. 44 +/- 0.01 nmol/min/mg. Delavirdine desalkylation among 23 human liver microsomal samples showed a meaningful correlation (r = 0.96) only with testosterone 6beta-hydroxylation, an indicator of CYP3A activity. Among ten human microsomal samples selected for uniform distribution of CYP3A activity, formation of MET-7 was strongly correlated with CYP3A activity (r = 0.95) and with delavirdine desalkylation (r = 0.98). Delavirdine desalkylation was catalyzed by cDNA-expressed CYP2D6 (KM 10.9 +/- 0.8 microM) and CYP3A4 (KM 5.4 +/- 1.4 microM); however, only CYP3A4 catalyzed formation of MET-7 and MET-7a. Quinidine inhibited human liver microsomal delavirdine desalkylation by about 20%, indicating a minor role of CYP2D6. These findings suggest the potential for clinical interaction with coadministered drugs that are metabolized by or influence the activity of CYP3A or CYP2D6.
使用来自多个物种的肝微粒体研究了地拉韦定的代谢情况，目的是比较不同物种间代谢物的形成，并确定负责地拉韦定代谢的酶。将10微摩尔[14C]地拉韦定与人空肠的S9组分或大鼠、人、狗或猴的肝微粒体一起孵育，随后进行高压液相色谱分析，结果显示不同物种间代谢物谱在质量上相似，均形成了三种主要代谢物。主要代谢物是去烷基地拉韦定；然而，MET - 7和MET - 7a（由高压液相色谱洗脱定义）的身份无法明确确定，但它们似乎是相关的吡啶羟基代谢物，很可能源自吡啶环的6'-羟基化。人、大鼠、猴和狗微粒体的地拉韦定去烷基化活性的表观KM范围为4.4至12.6微摩尔，而Vmax范围为0.07至0.60纳摩尔/分钟/毫克蛋白质，导致内在清除率范围很广（6 - 135微升/分钟/毫克蛋白质）。从多个人肝脏中收集的微粒体进行的地拉韦定去烷基化的特征为KM为6.8±0.8微摩尔，Vmax为0.44±0.01纳摩尔/分钟/毫克。23个人肝微粒体样品中的地拉韦定去烷基化仅与睾酮6β-羟基化（CYP3A活性的指标）显示出有意义的相关性（r = 0.96）。在为CYP3A活性均匀分布而选择的10个人微粒体样品中，MET - 7的形成与CYP3A活性（r = 0.95）和地拉韦定去烷基化（r = 0.98）密切相关。地拉韦定去烷基化由cDNA表达的CYP2D6（KM 10.9±0.8微摩尔）和CYP3A4（KM 5.4±1.4微摩尔）催化；然而，只有CYP3A4催化形成MET - 7和MET - 7a。奎尼丁抑制人肝微粒体地拉韦定去烷基化约20%，表明CYP2D6的作用较小。这些发现表明，地拉韦定与经CYP3A或CYP2D6代谢或影响其活性的共同给药药物之间可能存在临床相互作用。
