Chen C, Mistry G, Jensen B, Heizmann P, Timm U, van Brummelen P, Rakhit A K
Department of Clinical Pharmacology, Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA.
J Clin Pharmacol. 1996 Sep;36(9):799-808. doi: 10.1002/j.1552-4604.1996.tb04253.x.
These studies were conducted to evaluate the pharmacokinetics of several retinoids after meal consumption or vitamin A supplementation to establish a reference for future assessment of teratogenic risks of retinoid therapeutic agents. In the first study, 36 healthy young female volunteers consumed single meals containing vitamin A amounts ranging from 1,305 to 169,474 IU. In the second study, 24 other female volunteers took vitamin A supplements at a dose level of 5,000, 10,000, or 25,000 IU/day for 60 days. Plasma concentrations of tretinoin, isotretinoin, 4-oxo-tretinoin, and 4-oxo-isotretinoin in samples collected during the studies were analyzed using a high-performance liquid chromatography method with ultraviolet detection. Pharmacokinetic parameters for the retinoids were calculated using model-independent methods. Plasma concentrations of tretinoin were not altered by meal consumption or vitamin A supplementation. Plasma levels of 4-oxo-tretinoin were below the assay detection limit (0.3 ng/mL) in the majority of samples collected throughout the studies. Linear relationships between dose and maximum concentration (Cmax) and dose and area under the concentration-time curve (AUC) for isotretinoin and 4-oxo-isotretinoin were derived from data from the meal study. For the most bioavailable formulation used in the supplement study, daily ingestion of 5,000 IU of vitamin A caused increases of 141 +/- 53% and 171 +/- 77% from baseline in the 24-hour AUCs of isotretinoin and 4-oxo-isotretinoin, respectively. Dose-related increases in systemic exposure to retinoids were observed after ingestion of vitamin A by means of a meal or a supplement. Findings from these studies can be used as a basis for future safety evaluations of retinoid compounds.
进行这些研究是为了评估进食或补充维生素A后几种维甲酸的药代动力学，以便为未来评估维甲酸治疗药物的致畸风险建立参考。在第一项研究中，36名健康年轻女性志愿者食用了含维生素A量从1305至169474国际单位的单餐。在第二项研究中，另外24名女性志愿者以每天5000、10000或25000国际单位的剂量水平服用维生素A补充剂，持续60天。使用具有紫外检测的高效液相色谱法分析研究期间采集样本中的维甲酸、异维甲酸、4-氧代维甲酸和4-氧代异维甲酸的血浆浓度。使用非模型依赖方法计算维甲酸的药代动力学参数。进食或补充维生素A不会改变维甲酸的血浆浓度。在整个研究中采集的大多数样本中，4-氧代维甲酸的血浆水平低于检测限（0.3纳克/毫升）。异维甲酸和4-氧代异维甲酸的剂量与最大浓度（Cmax）以及剂量与浓度-时间曲线下面积（AUC）之间的线性关系源自进食研究的数据。对于补充剂研究中使用的生物利用度最高的制剂，每日摄入5000国际单位的维生素A分别使异维甲酸和4-氧代异维甲酸的24小时AUC较基线增加141±53%和171±77%。通过进食或补充剂摄入维生素A后，观察到维甲酸全身暴露量与剂量相关的增加。这些研究结果可作为未来维甲酸化合物安全性评估的基础。
