Pharmacokinetics and Drug Metabolism, Amgen, Inc., Seattle, WA 98119, USA.
Drug Metab Dispos. 2012 Oct;40(10):1927-34. doi: 10.1124/dmd.112.046169. Epub 2012 Jun 29.
The in vitro characterization of the inhibition potential of four representative maytansinoid species observed upon hepatic and/or tumor in vivo processing of antibody-maytansine conjugates (AMCs) with cleavable and noncleavable linkers is reported. We investigated the free maytansinoid species N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), (S)-methyl-DM1, and N(2')-deacetyl-N(2')-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) as representative cleavable linker catabolites and Lysine-N(ε)-N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate-DM1 (Lys-MCC-DM1) as the representative noncleavable linker catabolite. Studies with recombinant human cytochromes P450 (P450s) indicate CYP2D6, CYP3A4, and CYP3A5 are the primary isoforms responsible for the oxidative metabolism of DM1, (S)-methyl-DM1, and DM4. Lys-MCC-DM1 was not metabolized by any of the P450 isoforms studied. DM1 was shown to be a reversible inhibitor of CYP2C8 (K(i) = 11 ± 3 μM) and CYP2D6 (K(i) = 14 ± 2 μM). Lys-MCC-DM1 and (S)-methyl-DM1 showed no reversible or time-dependent inactivation of any of the P450s studied. DM1 and DM4 inactivated CYP3A from human liver microsomes with K(i)/k(inact) values of 4.8 ± 0.9 μM/0.035 ± 0.002 min(-1) and 3.3 ± 0.2 μM/0.114 ± 0.002 min(-1), respectively. DM1 and DM4 inactivated recombinant CYP3A4 with K(i)/k(inact) values of 3.4 ± 1.0 μM/0.058 ± 0.005 min(-1) and 1.4 ± 0.3 μM/0.117 ± 0.006 min(-1), respectively. Because of instability in plasma, further characterization of the DM1 and DM4 intramolecular and intermolecular disulfide conjugates observed in vivo is required before an accurate drug-drug interaction (DDI) prediction can be made. AMCs with noncleavable thioether-linked DM1 as the cytotoxic agent are predicted to have no potential for a DDI with any of the major human P450s studied.
报告了四种代表性美登素类似物在肝内和/或肿瘤体内处理具有可切割和不可切割接头的抗体-美登素偶联物（AMC）时的抑制潜力的体外特征。我们研究了游离美登素类似物 N(2')-去乙酰基-N(2')-(3-巯基-1-氧代丙基）-美登宁（DM1）、（S）-甲基-DM1 和 N(2')-去乙酰基-N(2')-(4-巯基-4-甲基-1-氧代戊基）-美登宁（DM4）作为代表性的可切割接头代谢产物，以及赖氨酸-N(ε)-N-琥珀酰亚胺基 4-(N-马来酰亚氨基甲基）环己烷-1-羧酸-DM1（Lys-MCC-DM1）作为代表性的不可切割接头代谢产物。用重组人细胞色素 P450（P450s）进行的研究表明，CYP2D6、CYP3A4 和 CYP3A5 是负责 DM1、（S）-甲基-DM1 和 DM4 氧化代谢的主要同工酶。Lys-MCC-DM1 未被研究的任何 P450 同工酶代谢。DM1 被证明是 CYP2C8（K(i) = 11 ± 3 μM）和 CYP2D6（K(i) = 14 ± 2 μM）的可逆抑制剂。Lys-MCC-DM1 和（S）-甲基-DM1 对研究的任何 P450 均未显示出可逆或时间依赖性失活。DM1 和 DM4 用来自人肝微粒体的 CYP3A 进行失活，K(i)/k(inact) 值分别为 4.8 ± 0.9 μM/0.035 ± 0.002 min(-1)和 3.3 ± 0.2 μM/0.114 ± 0.002 min(-1)。DM1 和 DM4 用重组 CYP3A4 进行失活，K(i)/k(inact) 值分别为 3.4 ± 1.0 μM/0.058 ± 0.005 min(-1)和 1.4 ± 0.3 μM/0.117 ± 0.006 min(-1)。由于在血浆中不稳定，在能够进行准确的药物相互作用（DDI）预测之前，需要对体内观察到的 DM1 和 DM4 分子内和分子间二硫键缀合物进行进一步的特征描述。具有不可切割硫醚连接的 DM1 作为细胞毒素的 AMCs 预计不会与研究的任何主要人 P450 发生潜在的药物相互作用。
