title: Periplocymarin is a potential natural compound for drug development: highly permeable with absence of P-glycoprotein efflux and cytochrome P450 inhibitions.
abstract: Periplocymarin, a cardiac glycoside isolated from Periploca sepium (P. sepium) and Periploca graeca (P. graeca), is a potential anti-cancer compound. The aim of the study was to investigate the potential for periplocymarin to interact with P-glycoprotein (P-gp) and to inhibit cytochrome P450s known to be expressed in the human small intestine. The in vitro and in situ permeability of periplocymarin were studied using Madin-Darby canine kidney (MDCK-II-WT) cells transfected with or without the human multidrug resistance (MDR1) gene and the single-pass perfused rat intestinal model. The cell system exhibited high functional activity and a net efflux ratio (NER) of 4.32 after transport of Rhodamine 123 (R123) (the P-gp substrate). Periplocymarin is highly permeable (Papp  > 10 × 10(-6) cm/s; Peff(rat)  > 5.09 × 10(-5) cm/s) and independent of P-gp influences. The NER at 100 μm periplocymarin (0.8) was unchanged in the presence of cyclosporine A (a non-specific P-gp inhibitor) (0.82). In the single-pass intestinal model, the Peff (rat) of 5 µg/ml periplocymarin (5.490 × 10(-5) cm/s) did not change in the presence of cyclosporine A (5.394 × 10(-5) cm/s). In the R123-inhibition assay, periplocymarin did not competitively inhibit P-gp. The inhibitory potential of periplocymarin on cytochrome P450 (CYP450s) was also studied. Periplocymarin (5, 50 μm) did not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. Thus, periplocymarin is unlikely to encounter drug-drug interactions with P-gp and CYP450s. Periplocymarin could be taken forward for further studies in drug development to test bioavailability, Phase II enzyme interactions and additional transporter interactions.
authors.affiliation: School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Nankai District, Tianjin, P.R. China, 300193.
authors.forename: Orleans N K
authors.initials: ON
authors.lastname: Martey
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xing
authors.forename: Fengchun
authors.initials: F
authors.lastname: Deng
authors.forename: Shan
authors.initials: S
authors.lastname: Feng
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Shi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D002301:Cardiac Glycosides / Q000493:pharmacokinetics* / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D010539:Permeability; D017208:Rats, Wistar
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002301:Cardiac Glycosides; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; C000593569:periplocymarin
keywords: CYP450s; P-gp; drug-drug interaction; periplocymarin; permeability