Interactions of casticin, ipriflavone, and resveratrol with serum albumin and their inhibitory effects on CYP2C9 and CYP3A4 enzymes.

Polyphenols are abundant molecules in the plant kingdom. They interact with several proteins in the body resulting in their complex biological effects. Previous studies demonstrated that polyphenols can interfere significantly with the pharmacokinetics of drugs by acting on their biotransformation, albumin-binding, and/or carrier-mediated transport. Casticin (CAS), ipriflavone (IPR), and resveratrol (RES) are well-known polyphenols often added to dietary supplements in high doses. In this study, we investigated the albumin-binding of these polyphenols by fluorescence spectroscopy, and their ability to displace the Sudlow's Site I ligand warfarin and the Site II ligand naproxen by ultrafiltration. Furthermore, the effects of CAS, IPR, and RES on CYP2C9 and CYP3A4 enzymes were examined, employing diclofenac and testosterone as substrates, respectively. Our main observations are the following: (1) Polyphenols formed stable complexes with albumin (K = 104-105 L/mol); (2) CAS and RES slightly displaced naproxen from human albumin, while albumin-binding of warfarin was not affected; (3) CAS and RES significantly inhibited CYP2C9, with CAS being as potent as the positive control warfarin; (4) each polyphenol significantly inhibited CYP3A4, with RES being stronger and CAS slightly weaker than the known inhibitor naringenin. Our results suggest that high intake of CAS and RES may interfere with the albumin-binding of Site II ligands as well as the metabolism of drugs by CYP2C9 and/or CYP3A4 enzymes, while large doses of IPR may affect the CYP3A4-catalyzed biotransformation of some drugs.

Pharmacokinetic interaction of diosmetin and silibinin with other drugs: Inhibition of CYP2C9-mediated biotransformation and displacement from serum albumin.

Diosmin and silibinin (SIL) are polyphenolic compounds which are the active components of several drugs and dietary supplements. After the oral administration of diosmin (flavonoid glycoside), only its aglycone diosmetin (DIO) reaches the systemic circulation. Both DIO and SIL form complexes with serum albumin and are able to inhibit several cytochrome P450 enzymes. Therefore, it is reasonable to hypothesize that these polyphenols may displace some drugs from serum albumin and inhibit their biotransformation, potentially leading to the disruption of drug therapy. In this study, the inhibitory action of DIO and SIL on CYP2C9-catalyzed metabolism of diclofenac to 4'-hydroxydiclofenac was examined, using warfarin as a positive control. Furthermore, interaction of DIO and SIL with human and bovine serum albumins as well as the displacement of warfarin from albumin by DIO and SIL were tested, employing steady-state fluorescence spectroscopy, fluorescence anisotropy, ultrafiltration, and molecular modeling. It is demonstrated that DIO and SIL are potent inhibitors of CYP2C9 enzyme and are able to displace the Site I ligand warfarin from human serum albumin. Because DIO and SIL may interfere with the pharmacokinetics of several drugs through both ways, we need to consider the potentially hazardous consequences of the consumption of diosmin or SIL together with other drugs.