RT Journal Article
SR Electronic
T1 In Vivo-Formed versus Preformed Metabolite Kinetics of <em>trans</em>-Resveratrol-3-sulfate and <em>trans</em>-Resveratrol-3-glucuronide
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1993
OP 2001
DO 10.1124/dmd.112.046417
VO 40
IS 10
A1 Sharan, Satish
A1 Iwuchukwu, Otito F.
A1 Canney, Daniel J.
A1 Zimmerman, Cheryl L.
A1 Nagar, Swati
YR 2012
UL http://dmd.aspetjournals.org/content/40/10/1993.abstract
AB Metabolites in safety testing have gained a lot of attention recently. Regulatory agencies have suggested that the kinetics of preformed and in vivo-formed metabolites are comparable. This subject has been a topic of debate. We have compared the kinetics of in vivo-formed with preformed metabolites. trans-3,5,4′-Trihydroxystilbene [trans-resveratrol (RES)] and its two major metabolites, resveratrol-3-sulfate (R3S) and resveratrol-3-glucuronide (R3G) were used as model substrates. The pharmacokinetics (PK) of R3S and R3G were characterized under two situations. First, the pharmacokinetics of R3S and R3G were characterized (in vivo-formed metabolite) after administration of RES. Then, synthetic R3S and R3G were administered (preformed metabolite) and their pharmacokinetics were characterized. PK models were developed to describe the data. A three-compartment model for RES, a two-compartment model for R3S (preformed), and an enterohepatic cycling model for R3G (preformed) was found to describe the data well. These three models were further combined to build a comprehensive PK model, which was used to perform simulations to predict in vivo-formed metabolite kinetics. Comparisons were made between in vivo-formed and preformed metabolite kinetics. Marked differences were observed in the kinetics of preformed and in vivo-formed metabolites.