新型高效抗巨细胞病毒分子CMV423（2-氯-3-吡啶-3-基-5,6,7,8-四氢中氮茚-1-甲酰胺）的体外代谢及药物相互作用潜力

In vitro metabolism and drug interaction potential of a new highly potent anti-cytomegalovirus molecule, CMV423 (2-chloro 3-pyridine 3-yl 5,6,7,8-tetrahydroindolizine I-carboxamide).

作者信息

Bournique B, Lambert N, Boukaiba R, Martinet M

机构信息

Drug Metabolism and Pharmacokinetics Department, Aventis Pharma, 13 Quai Jules Guesde, BP 14, 94403 Vitry sur Seine Cedex, France.

出版信息

Br J Clin Pharmacol. 2001 Jul;52(1):53-63. doi: 10.1046/j.0306-5251.2001.01413.x.

DOI:10.1046/j.0306-5251.2001.01413.x

PMID:11453890

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2014500/

Abstract

AIMS

To identify the enzymes involved in the metabolism of CMV423, a new anticytomegalovirus molecule, to evaluate its in vitro clearance and to investigate its potential involvement in drug/drug interactions that might occur in the clinic.

METHODS

The enzymes involved in and the kinetics of CMV423 biotransformation were determined using pools of human liver subcellular fractions and heterologously expressed human cytochromes P450 (CYP) and FMO. The effect of CMV423 on CYP probe activities as well as on indinavir and AZT metabolism was determined, and 26 drugs were tested for their potential to inhibit or activate CMV423 metabolism.

RESULTS

CMV423 was oxidized by CYP and not by FMO or cytosolic enzymes. The Km values for 8-hydroxylation to rac-RPR 127025, an active metabolite, and subsequent ketone formation by human liver microsomes were 44 +/- 13 microM and 47 +/- 11 microM, respectively, with corresponding Vmax/Km ratios of 14 and 4 microl min(-1) nmol(-1) P450. Inhibition with selective CYP inhibitors indicated that CYP1A2 was the main isoform involved, with some participation from CYP3A. Expressed human CYP1A1, 1A2, 2C9, 3A4 and 2C8 catalysed rac-RPR 127025 formation with Km values of < 10 microM, 50 +/- 21 microM, 55 +/- 19 microM, circa 282 +/- 61 microM and circa 1450 microM, respectively. CYP1B1, 2A6, 2B6, 2C19, 2D6, 2E1 or 3A5 did not catalyse the reaction to any detectable extent. CYP1A1 and 3A4 also catalysed ketone formation from rac-RPR 127025. In human liver microsomes, CMV423 at 1 and 10 microM inhibited CYP1A2 activity up to 31% and 63%, respectively, CYP3A4 activity up to 40% (10 microM) and CYP2C9 activity by 35% (1 and 10 microM). No effect was observed on CYP2A6, 2D6 and 2E1 activities. CMV423 had no effect on indinavir and AZT metabolism. Amongst 26 drugs tested, none inhibited CMV423 metabolism in vitro at therapeutic concentrations.

CONCLUSIONS

CMV423 is mainly metabolized by CYP1A2 and 3A4. Its metabolism should not be saturable at the targeted therapeutic concentrations range (Cmax < 1 microM). CMV423 will probably affect CYP1A2 and 1A1 activities in vivo to some extent, but no other drug-drug interactions are expected.

摘要

目的

鉴定参与新型抗巨细胞病毒分子CMV423代谢的酶，评估其体外清除率，并研究其在临床可能发生的药物/药物相互作用中的潜在影响。

方法

使用人肝脏亚细胞组分池以及异源表达的人细胞色素P450（CYP）和黄素单加氧酶（FMO）确定参与CMV423生物转化的酶及其动力学。测定CMV423对CYP探针活性以及茚地那韦和齐多夫定代谢的影响，并测试26种药物抑制或激活CMV423代谢的潜力。

结果

CMV423由CYP氧化，而非FMO或胞质酶。人肝微粒体将其8-羟基化生成活性代谢物rac-RPR 127025以及随后形成酮的Km值分别为44±13μM和47±11μM，相应的Vmax/Km比值分别为14和4μl min⁻¹ nmol⁻¹ P450。用选择性CYP抑制剂进行抑制表明，CYP1A2是主要参与的同工酶，CYP3A也有一定参与。表达的人CYP1A1、1A2、2C9、3A4和2C8催化rac-RPR 127025形成，Km值分别<10μM、50±21μM、55±19μM、约282±61μM和约1450μM。CYP1B1、2A6、2B6、2C19、2D6、2E1或3A5在任何可检测程度上均未催化该反应。CYP1A1和3A4也催化rac-RPR 127025形成酮。在人肝微粒体中，1μM和10μM的CMV423分别使CYP1A2活性抑制高达31%和63%，CYP3A4活性抑制高达40%（10μM），CYP2C9活性抑制35%（1μM和10μM）。未观察到对CYP2A6、2D6和2E1活性的影响。CMV423对茚地那韦和齐多夫定代谢无影响。在所测试的26种药物中，在治疗浓度下体外均未抑制CMV423代谢。