PT  - JOURNAL ARTICLE
AU  - Satish Sharan
AU  - Otito Frances Iwuchukwu
AU  - Daniel J Canney
AU  - Cheryl L. Zimmerman
AU  - Swati NAGAR
TI  - In-vivo Formed Versus Preformed Metabolite Kinetics of Trans-resveratrol-3-sulfate (R3S) and Trans-resveratrol-3-glucuronide (R3G)
AID  - 10.1124/dmd.112.046417
DP  - 2012 Jul 17
TA  - Drug Metabolism and Disposition
PG  - dmd.112.046417
4099  - http://dmd.aspetjournals.org/content/early/2012/07/17/dmd.112.046417.short
4100  - http://dmd.aspetjournals.org/content/early/2012/07/17/dmd.112.046417.full
AB  - Metabolites in safety testing (MIST) have gained a lot of attention recently. Regulatory bodies have made recommendations where it is assumed that the kinetics of preformed and in vivo formed metabolites are similar. This has been a topic of debate. We have compared the kinetics of in vivo formed and 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 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. Pharmacokinetic (PK) models were developed to describe the data. A three compartment model for RES, 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.