Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA.
Drug Metab Dispos. 2012 Oct;40(10):1993-2001. doi: 10.1124/dmd.112.046417. Epub 2012 Jul 17.
Metabolites in safety testing have gained a lot of attention recently. Regulatory agencies have suggested that the kinetics of preformed and in vivo-formed metabolites are comparable. This subject has been a topic of debate. We have compared the kinetics of in vivo-formed with preformed metabolites. trans-3,5,4'-Trihydroxystilbene [trans-resveratrol (RES)] and its two major metabolites, resveratrol-3-sulfate (R3S) and resveratrol-3-glucuronide (R3G) were used as model substrates. The pharmacokinetics (PK) of R3S and R3G were characterized under two situations. First, the pharmacokinetics of R3S and R3G were characterized (in vivo-formed metabolite) after administration of RES. Then, synthetic R3S and R3G were administered (preformed metabolite) and their pharmacokinetics were characterized. PK models were developed to describe the data. A three-compartment model for RES, a two-compartment model for R3S (preformed), and an enterohepatic cycling model for R3G (preformed) was found to describe the data well. These three models were further combined to build a comprehensive PK model, which was used to perform simulations to predict in vivo-formed metabolite kinetics. Comparisons were made between in vivo-formed and preformed metabolite kinetics. Marked differences were observed in the kinetics of preformed and in vivo-formed metabolites.
代谢产物在安全测试中受到了广泛关注。监管机构建议预先形成和体内形成的代谢物的动力学具有可比性。这个问题一直存在争议。我们比较了体内形成的代谢物和预先形成的代谢物的动力学。反式-3,5,4'-三羟基二苯乙烯[反式白藜芦醇（RES）]及其两种主要代谢物，白藜芦醇-3-硫酸盐（R3S）和白藜芦醇-3-葡萄糖醛酸苷（R3G）被用作模型底物。在两种情况下对 R3S 和 R3G 的药代动力学（PK）进行了特征描述。首先，在给予 RES 后对 R3S 和 R3G 的药代动力学（体内形成的代谢物）进行了特征描述。然后，给予合成的 R3S 和 R3G（预先形成的代谢物）并对其药代动力学进行了特征描述。建立了 PK 模型来描述数据。发现 RES 的三房室模型、R3S（预先形成的）的二房室模型和 R3G（预先形成的）的肠肝循环模型能够很好地描述数据。这三个模型进一步组合成一个综合 PK 模型，用于进行模拟预测体内形成的代谢物动力学。比较了体内形成的代谢物和预先形成的代谢物的动力学。预先形成的代谢物和体内形成的代谢物的动力学存在明显差异。
