Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, Beijing, China (X.-M.Z., Y.-H.Z., W.-B.X., H.L.); and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (C.L.).
Drug Metab Dispos. 2013 Nov;41(11):1914-22. doi: 10.1124/dmd.113.053199. Epub 2013 Aug 23.
Naturally occurring furanocoumarin compounds psoralen (PRN) and isopsoralen (IPRN) are bioactive constituents found in herbaceous plants. They are widely used as active ingredients in several Chinese herbal medicines. In this study, the CYP1A2 inhibitory potential of PRN and IPRN was investigated in rats in vitro and in vivo as well as in human liver microsomes. Both compounds exhibited reversible and time-dependent inhibition toward rat microsomal cyp1a2. The IC(50), k(inact), and K(I) values were 10.4 ± 1.4 μM, 0.060 ± 0.002 min(-1), and 1.13 ± 0.12 μM for PRN, and 7.1 ± 0.6 μM, 0.10 ± 0.01 min(-1), and 1.95 ± 0.31 μM for IPRN, respectively. In human liver microsomal incubations, potent reversible CYP1A2 inhibition was observed for both compounds, with IC(50) values of 0.26 ± 0.01 μM and 0.22 ± 0.03 μM for PRN and IPRN, respectively. However, time-dependent inhibition was only observed for IPRN, with kinact and KI values of 0.050 ± 0.002 min(-1) and 0.40 ± 0.06 μM, respectively. Coadministration with PRN or IPRN significantly inhibited cyp1a2 activity in rats, with the area under the curve (AUC) of phenacetin increasing more than 5-fold. Simcyp simulation predicted that PRN would cause 1.71- and 2.12-fold increases in the phenacetin AUC in healthy volunteers and smokers, respectively. IPRN, on the other hand, would result in 3.24- and 5.01-fold increases in phenacetin AUCs in healthy volunteers and smokers, respectively. These findings represent the first detailed report comparing the potential drug-drug interactions of PRN and IPRN, and provide useful information for balancing safe and efficacious doses of PRN and IPRN.
天然呋喃香豆素化合物补骨脂素（PRN）和异补骨脂素（IPRN）是草本植物中的生物活性成分。它们被广泛用作几种中药的有效成分。在这项研究中，我们在大鼠体内和体外以及人肝微粒体中研究了 PRN 和 IPRN 对 CYP1A2 的抑制潜力。这两种化合物对大鼠微粒体 CYP1A2 均表现出可逆和时间依赖性抑制。PRN 的 IC50、k(inact)和 K(I)值分别为 10.4 ± 1.4 μM、0.060 ± 0.002 min(-1)和 1.13 ± 0.12 μM，而 IPRN 的分别为 7.1 ± 0.6 μM、0.10 ± 0.01 min(-1)和 1.95 ± 0.31 μM。在人肝微粒体孵育中，这两种化合物均表现出强效的可逆 CYP1A2 抑制，IC50 值分别为 0.26 ± 0.01 μM 和 0.22 ± 0.03 μM。然而，只有 IPRN 观察到时间依赖性抑制，kinact 和 KI 值分别为 0.050 ± 0.002 min(-1)和 0.40 ± 0.06 μM。PRN 或 IPRN 的共同给药显著抑制了大鼠 CYP1A2 活性，使非那西汀的 AUC 增加了 5 倍以上。Simcyp 模拟预测，PRN 将分别使健康志愿者和吸烟者中非那西汀 AUC 增加 1.71 倍和 2.12 倍。另一方面，IPRN 将分别使健康志愿者和吸烟者中非那西汀 AUC 增加 3.24 倍和 5.01 倍。这些发现代表了比较 PRN 和 IPRN 潜在药物相互作用的第一份详细报告，并为平衡 PRN 和 IPRN 的安全有效剂量提供了有用的信息。
