Rohatagi S, Barrett J S
DuPont Merck Pharmaceuticals, Stine-Haskell Research Center, Newark, DE 19714, USA.
Am J Ther. 1997 May-Jun;4(5-6):189-98. doi: 10.1097/00045391-199705000-00005.
Disposition of ipriflavone, an agent indicated for the treatment of osteoporosis, is highly variable after oral administration. Ipriflavone has five major metabolites (M1, M2, M3, M4, and M5). The metabolites M2 and M5 have activity and are major metabolic constituents in humans. Hence, it is important to characterize both ipriflavone and metabolites simultaneously. Our purpose was to develop an integrated pharmacokinetic/metabolic model that simultaneously predicts plasma concentrations of ipriflavone and metabolites after a single oral administration.
The model was based on the reported metabolic conversion of ipriflavone to M1, M3, and M4; subsequent conversion of M4 to M5; and conversion of both M1 and M3 to M2 in rats. The further conversion of M5 to M6 and M7 was ignored, as this conversion represents an insignificant portion of the total metabolite pool. The input function was described by a first-order constant. Each analyte required two-compartment disposition. The elimination/nonmetabolic constants for each analyte accounted for urinary elimination. Plasma concentration data from a pilot pharmacokinetic study in which 16 healthy male volunteers were administered 200 mg of an ipriflavone corn suspension were used to examine the predictability of this model.
The coefficient of determination was 0.99, and model selection criterion was 3.7 for mean data fits supporting the goodness-of-fit and predictability of the model. The model also predicted negligible urinary recoveries for ipriflavone, M1, M3, and M4; M2 and M5 had high urinary recoveries. The metabolic conversion constant from M3 to M2 was negligible. Divergence from the proposed pathway may be attributed to the species differences in metabolism between humans and rats.
Model predictions supported the improvement in bioavailability with corn-oil suspension compared to the conventional oral tablet. Future model applications may also help identify significant covariates (i.e., age, gender, and disease state) in proposed clinical trials.
依普黄酮是一种用于治疗骨质疏松症的药物，口服给药后其处置存在高度变异性。依普黄酮有五种主要代谢物（M1、M2、M3、M4和M5）。代谢物M2和M5具有活性，是人体内主要的代谢成分。因此，同时对依普黄酮和代谢物进行表征很重要。我们的目的是建立一个综合的药代动力学/代谢模型，该模型能够同时预测单次口服给药后依普黄酮和代谢物的血浆浓度。
该模型基于已报道的依普黄酮在大鼠体内向M1、M3和M4的代谢转化；随后M4向M5的转化；以及M1和M3两者向M2的转化。忽略了M5向M6和M7的进一步转化，因为这种转化在总代谢物池中所占比例微不足道。输入函数用一级常数描述。每种分析物需要两室处置。每种分析物的消除/非代谢常数用于说明尿排泄情况。在一项初步药代动力学研究中，16名健康男性志愿者服用了200 mg依普黄酮玉米混悬液，利用该研究中的血浆浓度数据来检验该模型的预测能力。
决定系数为0.99，模型选择标准对于支持模型拟合优度和预测能力的平均数据拟合为3.7。该模型还预测依普黄酮、M1、M3和M4的尿回收率可忽略不计；M2和M5的尿回收率较高。从M3到M2的代谢转化常数可忽略不计。与所提出途径的差异可能归因于人和大鼠在代谢方面的种属差异。
模型预测支持了与传统口服片剂相比，玉米油混悬液可提高生物利用度。未来模型的应用也可能有助于在拟进行的临床试验中识别重要的协变量（即年龄、性别和疾病状态）。
