Formelli F, Clerici M, Campa T, Di Mauro M G, Magni A, Mascotti G, Moglia D, De Palo G, Costa A, Veronesi U
Instituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
J Clin Oncol. 1993 Oct;11(10):2036-42. doi: 10.1200/JCO.1993.11.10.2036.
Monitoring of fenretinide (4HPR) levels, kinetics, and effects on retinal was performed in patients who participated in a phase I trial and who continued to be treated for 5 years as phase III trial patients. Accumulation of 4HPR in the breast was also assessed.
Plasma concentrations of 4HPR, of its main metabolite N-(4-methoxyphenyl)retinamide (4MPR), and of retinol were assayed by high-performance liquid chromatography (HPLC) in breast cancer patients treated orally with 4HPR 200 mg/d for 5 years with a 3-day drug interruption at the end of each month.
4HPR, at 200 mg/d, resulted in average 4HPR plasma levels of approximately 1 mumol/L, which remained steady and caused steady retinol level reduction; 4MPR levels, similar to those of 4HPR, slightly but significantly increased during the first 35 months, but at 5 years they were similar to those at 5 months. During daily treatment, baseline retinol concentrations were reduced by 71%; after a 3-day drug interruption, all patients recovered and the mean reduction was 38%. After discontinuation of 5-year treatment, 4HPR and 4MPR half-lives (t1/2 beta) were 27 and 54 hours, respectively, similar to those reported after 28 daily treatments. After 6 and 12 months, the concentrations of 4HPR were at the limit of detectability (0.01 mumol/L), whereas those of 4MPR were five times higher. Baseline retinol concentrations were already recovered after 1 month. Accumulation of this retinoid in the breast was evidenced by concentrations of 4HPR and 4MPR in nipple discharge and in breast biopsies that were 10 and 20 times higher, respectively, than those found in plasma.
4HPR, at 200 mg/d for 5 years, resulted in constant drug plasma levels and constant retinol level reduction. After treatment interruption, 4HPR plasma concentrations decreased at the limit of detectability at 6 months and baseline retinol plasma concentrations were recovered after 1 month.
对参与Ⅰ期试验且作为Ⅲ期试验患者继续接受5年治疗的患者进行了非维生素A酸（4HPR）水平、动力学及其对视网膜影响的监测。还评估了4HPR在乳腺中的蓄积情况。
采用高效液相色谱法（HPLC）测定口服4HPR 200mg/d、持续5年且每月末停药3天的乳腺癌患者血浆中4HPR、其主要代谢产物N-(4-甲氧基苯基)视黄酰胺（4MPR）以及视黄醇的浓度。
4HPR剂量为200mg/d时，血浆中4HPR平均水平约为1μmol/L，保持稳定，并导致视黄醇水平持续降低；4MPR水平与4HPR水平相似，在最初35个月内略有但显著升高，但在5年时与5个月时相似。在每日治疗期间，基线视黄醇浓度降低了71%；停药3天后，所有患者均恢复，平均降低幅度为38%。5年治疗停药后，4HPR和4MPR的半衰期（t1/2β）分别为27小时和54小时，与28天每日治疗后报告的半衰期相似。6个月和12个月后，4HPR浓度处于可检测极限（0.01μmol/L），而4MPR浓度则高出5倍。1个月后基线视黄醇浓度已恢复。乳头溢液和乳腺活检组织中4HPR和4MPR的浓度分别比血浆中高10倍和20倍，证明了这种类视黄醇在乳腺中的蓄积。
4HPR剂量为200mg/d、持续5年，导致药物血浆水平恒定，视黄醇水平持续降低。治疗中断后，4HPR血浆浓度在6个月时降至可检测极限，1个月后基线视黄醇血浆浓度恢复。
