Modulation of P450-dependent ifosfamide pharmacokinetics: a better understanding of drug activation in vivo.
Modulation of P450-dependent ifosfamide pharmacokinetics: a better understanding of drug activation in vivo.
复制标题
P450 依赖性异环磷酰胺药代动力学的调节：更好地了解体内药物激活。
DOI：
10.1038/bjc.1998.295
复制
发表时间：
1998
影响因子：
8.8
通讯作者：
Waxman,DJ
中科院分区：
文献类型：
--
作者：
Brain,EG;Yu,LJ;Gustafsson,K;Drewes,P;Waxman,DJ
抗癌前药异环磷酰胺（IF）通过两种替代途径被肝脏P450酶代谢。IF被活化为4-羟基IF（4-OH-IF），最终产生烷基化芥子异磷酰胺，而IF N-脱氯乙基化使药物失活并产生神经毒性代谢物氯乙醛（CA）。在离体大鼠肝微粒体中，这两种反应均由多种肝P450酶体外催化。本药代动力学研究探讨了使用成年雄性Fischer 344大鼠模型在体内调节这些替代IF代谢途径的可能性。用IF单独或与各种P450诱导剂和抑制剂联合治疗大鼠，以改善药物活化和药物失活之间的平衡。计算4-OH-IF和CA的血浆浓度、曲线下面积（AUC）和半衰期，以估计IF活化和失活/灭活的程度。高剂量苯巴比妥（PB）预处理4天诱导肝脏P450 2B酶显著降低IF进行4-羟基化的分数（AUC（4-OH-IF）/AUC（4-OH-IF）+ AUC（CA）），占总代谢的37%至22%（P< 0.05），与体外研究结果一致，即PB诱导的P450酶2B 1在IF N-脱氯乙基化中起主要作用。用P450 3A诱导剂地塞米松预处理成比例地降低了两种IF代谢物的AUC，对经历代谢活化的IF分数没有任何净影响。相比之下，P450 2B 1抑制剂甲吡酮优先增加3天低剂量PB诱导大鼠4-羟基化途径的AUC，从而将通过活化途径代谢的IF的总分数从36%增加到54%（P< 0.05），而P450抑制剂奥芬那君和三乙酰竹桃霉素对AUC值没有显著影响。这些研究结果表明，P450 2B和3A酶在体内催化这些IF代谢途径中的特定作用，并证明了以治疗有用的方式调节IF替代代谢途径的潜力。这些研究还强调了IF与调节肝P450酶水平的药物和其他化合物联合给药期间可能发生的几种临床相关药物相互作用。
The anti-cancer prodrug ifosfamide (IF) is metabolized by liver P450 enzymes by two alternative pathways. IF is activated to 4-hydroxy IF (4-OH-IF), which ultimately yields the alkylating mustard isophosphoramide, whereas IF N-dechlororethylation inactivates the drug and produces the neurotoxic metabolite chloroacetaldehyde (CA). Both reactions are catalysed by multiple liver P450 enzymes in vitro in isolated rat liver microsomes. The present pharmacokinetic study investigates the potential for modulation of these alternative pathways of IF metabolism in vivo using the adult male Fischer 344 rat model. Rats were treated with IF alone or in conjunction with various P450 inducers and inhibitors in an effort to improve the balance between drug activation and drug inactivation. Plasma concentrations, areas under the curve (AUC) and half-lives were calculated for 4-OH-IF and CA, allowing estimations of the extent of IF activation and deactivation/toxification. Induction of liver P450 2B enzymes by 4-day high-dose phenobarbital (PB) pretreatment significantly decreased the fraction of IF undergoing 4-hydroxylation (AUC (4-OH-IF)/AUC (4-OH-IF)+ AUC (CA)), from 37% to 22% of total metabolism (P< 0.05), consistent with in vitro findings that the PB-inducible P450 enzyme 2B1 plays a major role in IF N-dechloroethylation. Pretreatment with the P450 3A inducer dexamethasone proportionally decreased the AUC for both IF metabolites, without any net impact on the fraction of IF undergoing metabolic activation. By contrast, the P450 2B1 inhibitor metyrapone preferentially increased the AUC for the 4-hydroxylation pathway in 3-day low-dose PB-induced rats, thereby increasing the total fraction of IF metabolized via the activation pathway from 36% to 54%(P< 0.05), whereas the P450 inhibitors orphenadrine and troleandomycin had no significant affect on AUC values. These findings demonstrate specific roles for P450 2B and 3A enzymes in catalysing these pathways of IF metabolism in vivo, and demonstrate the potential for modulation of IF's alternative metabolic pathways in a therapeutically useful manner. These studies also highlight several clinically relevant drug interactions that may occur during concomitant administration of IF with drugs and other compounds that modulate hepatic P450 enzyme levels.