Kurowski V, Cerny T, Küpfer A, Wagner T
Klinik für Innere Medizin, Medizinische Universität Lübeck, Federal Republic of Germany.
J Cancer Res Clin Oncol. 1991;117 Suppl 4(Suppl 4):S148-53. doi: 10.1007/BF01613221.
The initial metabolism of ifosfamide (IF) consists of two different pathways: enzymatic hydroxylation at carbon-4 forms the cytostatically active metabolite 4-OH-IF ("activated ifosfamide") whereas side-chain oxidation results in the liberation of chloroacetaldehyde, a compound with possible neurotoxic properties. The pharmacokinetics of ifosfamide and its activated form were investigated in 12 cancer patients, who received both oral and i.v. treatment in a randomized sequence on days 1 and 3 at a dose of 1 g/m2 (n = 7) or 1.5 g/m2 (n = 5). In 3 patients the pharmacokinetics of chloroacetaldehyde were also investigated. After oral application, ifosfamide absorption proceeded rapidly, the oral bioavailability was 0.92. Independent of the route of ifosfamide application on day 1, the terminal half-life on day 3 (when the drug was given by the alternative route) was decreased in 6 out of the 12 patients, thus indicating self-induction of hepatic metabolism. 4-OH-IF was already present 20 min after ifosfamide administration. In the individual patient the concentrations of 4-OH-IF were always higher after oral than after i.v. IF application: the mean p.o.:i.v. ratios for cmax and the area under the concentration/time curve were 2.3 and 1.7 respectively (P less than 0.05). In a first series of 3 patients the chloroacetaldehyde concentrations measured after oral ifosfamide application were about twice as high as those when the drug was given intravenously. These results indicate that (in comparison to the i.v. route) orally administered ifosfamide may be more cancerotoxic but also leads to higher levels of chloroacetaldehyde. This would explain the neurotoxic side-effects previously seen after oral administration of comparatively low ifosfamide doses.
异环磷酰胺（IF）的初始代谢包括两条不同途径：4位碳原子的酶促羟基化形成具有细胞抑制活性的代谢产物4-羟基异环磷酰胺（“活化异环磷酰胺”），而侧链氧化则导致具有潜在神经毒性的氯乙醛释放。在12例癌症患者中研究了异环磷酰胺及其活化形式的药代动力学，这些患者在第1天和第3天以随机顺序接受口服和静脉内治疗，剂量为1 g/m²（n = 7）或1.5 g/m²（n = 5）。在3例患者中还研究了氯乙醛的药代动力学。口服给药后，异环磷酰胺吸收迅速，口服生物利用度为0.92。无论第1天异环磷酰胺的给药途径如何，在第3天（当通过另一种途径给药时），12例患者中有6例的终末半衰期缩短，这表明肝脏代谢存在自身诱导作用。异环磷酰胺给药后20分钟即可检测到4-羟基异环磷酰胺。在个体患者中，口服异环磷酰胺后4-羟基异环磷酰胺的浓度总是高于静脉内给药后：cmax和浓度/时间曲线下面积的平均口服：静脉内比率分别为2.3和1.7（P＜0.05）。在最初的3例患者系列中，口服异环磷酰胺后测得的氯乙醛浓度约为静脉内给药时的两倍。这些结果表明，与静脉内途径相比，口服异环磷酰胺可能具有更强的抗癌毒性，但也会导致更高水平的氯乙醛。这可以解释先前在口服相对低剂量异环磷酰胺后出现的神经毒性副作用。
