title: Identification and characterization of psoralen and isopsoralen as potent CYP1A2 reversible and time-dependent inhibitors in human and rat preclinical studies.
abstract: 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.
authors: 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.).
authors: Xiao-Mei
authors: XM
authors: Zhuang
authors: Yu-Huan
authors: YH
authors: Zhong
authors: Wei-Bin
authors: WB
authors: Xiao
authors: Hua
authors: H
authors: Li
authors: Chuang
authors: C
authors: Lu
mesh_terms: D000818:Animals; D019540:Area Under Curve; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions / Q000502:physiology; D005363:Ficusin / Q000494:pharmacology*; D011564:Furocoumarins / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010615:Phenacetin / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D011564:Furocoumarins; C011659:angelicin; D019388:Cytochrome P-450 CYP1A2; D010615:Phenacetin; D005363:Ficusin