Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA.
J Clin Pharmacol. 2010 Nov;50(11):1330-8. doi: 10.1177/0091270009360041. Epub 2010 Mar 2.
Plasma 4β-hydroxycholesterol (4βHC) has been proposed as an endogenous marker of cytochrome P450 3A (CYP3A). To assess its utility as a CYP3A metric, a pharmacokinetic model, assuming no alteration in cholesterol plasma concentrations, was developed to simulate the effect of CYP3A induction and inhibition on 4βHC plasma levels under different treatment durations. By incorporating the long plasma half-life of 4βHC (~17 days) into the model, the inductive effect of 2 known inducers (carbamazepine and rifampicin) reported in the literature was adequately described. Furthermore, the simulations showed that it was possible to resolve none, weak, moderate, and potent inducers within 2 weeks of dosing. On the other hand, simulations indicated that at least 2 weeks of dosing would be needed to detect the potent inhibition of CYP3A (maximal ~40% decrease in 4βHC plasma levels). Greater differentiation of weak, moderate, and potent CYP3A inhibitors would require a longer duration of dosing (≥1 month). When considering 4βHC as a metric, one should take into account assay precision, the anticipated magnitude of the effect, and the feasibility of dosing beyond 2 weeks. In addition, the 4βHC metric needs to be normalized with the corresponding cholesterol plasma level in the same subject.
血浆 4β-羟基胆固醇（4βHC）已被提议作为细胞色素 P450 3A（CYP3A）的内源性标志物。为了评估其作为 CYP3A 度量的效用，开发了一个药代动力学模型，假设胆固醇血浆浓度没有改变，以模拟 CYP3A 诱导和抑制在不同治疗持续时间下对 4βHC 血浆水平的影响。通过将 4βHC 的长血浆半衰期（~17 天）纳入模型，充分描述了文献中报道的 2 种已知诱导剂（卡马西平和利福平）的诱导作用。此外，模拟表明，在 2 周的给药时间内，可以分辨出无、弱、中、强诱导剂。另一方面，模拟表明，至少需要 2 周的给药时间才能检测到 CYP3A 的强抑制（最大约 40%降低 4βHC 血浆水平）。要区分弱、中、强 CYP3A 抑制剂，需要更长的给药时间（≥1 个月）。当考虑将 4βHC 作为度量时，应考虑测定精度、预期的影响幅度以及超过 2 周的给药可行性。此外，4βHC 度量需要与同一受试者的相应胆固醇血浆水平进行归一化。
