Brinker A, Kisro J, Letsch C, Brüggemann S K, Wagner T
Department of Hematology/Oncology, Medical University of Lübeck, Germany.
Int J Clin Pharmacol Ther. 2002 Aug;40(8):376-81. doi: 10.5414/cpp40376.
This study focuses on the pharmacokinetics of trofosfamide (TRO) and metabolites after oral administration of TRO.
Twelve patients with solid tumors and non-Hodgkin lymphomas were treated with 450 mg TRO orally for 7 days. TRO and the stable metabolites ifosfamide (IFO), cyclophosphamide (CYC), 2- and 3-dechloroethylifosfamide (2-DCE, 3-DCE) were determined by GC and the sum of the 4-OH-metabolites was measured by HPLC.
A fast metabolism of TRO with a half-life of about 1 h was observed. IFO was the main stable metabolite, whereas CYC was only detected in minor quantities. The peak levels and the AUC of the 4-OH-metabolites were 9.5 and 4.3 times higher than observed after an equimolar IFO dose. Only 6% of the administered dose was recovered in urine within 24 hours as stable metabolites. TRO was under limit of detection.
Our results confirm that dechloroethylation of TRO to IFO is a major metabolic pathway. Additionally, we found considerable 4-hydroxylation not shown previously. With respect to the low levels of IFO and CYC observed, the sum of 4-OH-metabolites cannot be explained by hydroxylation of these metabolites only. Hence, we assume a direct 4-hydroxylation of TRO occurring to a high extent. Bioavailability of TRO could not be calculated directly, because TRO is only available as an oral formulation. The bioavailability of oral IFO, however, is reported to be almost 100%. Therefore, after normalization of the dose, a bioavailability of 32% for IFO after oral TRO could be calculated. Thus, in contrast to previous reports, direct 4-hydroxylation of TRO seems to be the main metabolic pathway.
本研究聚焦于口服曲磷胺（TRO）后其及其代谢产物的药代动力学。
12例实体瘤和非霍奇金淋巴瘤患者口服450 mg TRO，疗程7天。采用气相色谱法测定TRO及其稳定代谢产物异环磷酰胺（IFO）、环磷酰胺（CYC）、2-和3-去氯乙基异环磷酰胺（2-DCE、3-DCE），采用高效液相色谱法测定4-羟基代谢产物的总量。
观察到TRO代谢迅速，半衰期约为1小时。IFO是主要的稳定代谢产物，而CYC仅少量检出。4-羟基代谢产物的峰值水平和曲线下面积比等摩尔剂量的IFO给药后分别高9.5倍和4.3倍。24小时内尿液中仅6%的给药剂量以稳定代谢产物形式回收。TRO低于检测限。
我们的结果证实TRO脱氯乙基化为IFO是主要代谢途径。此外，我们发现了此前未显示的大量4-羟基化现象。鉴于观察到的IFO和CYC水平较低，4-羟基代谢产物的总量不能仅通过这些代谢产物的羟基化来解释。因此，我们推测TRO直接发生4-羟基化的程度很高。由于TRO仅以口服制剂形式提供，无法直接计算其生物利用度。然而，据报道口服IFO的生物利用度几乎为100%。因此，剂量归一化后，口服TRO后IFO的生物利用度可计算为32%。因此，与之前的报道相反，TRO的直接4-羟基化似乎是主要代谢途径。
