In vivo-formed versus preformed metabolite kinetics of trans-resveratrol-3-sulfate and trans-resveratrol-3-glucuronide.
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.
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA. swati.nagar@temple.edu
Satish
S
Sharan
Otito F
OF
Iwuchukwu
Daniel J
DJ
Canney
Cheryl L
CL
Zimmerman
Swati
S
Nagar
D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D020719:Glucuronides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D007269:Injections, Intra-Arterial; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013431:Sulfates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D020719:Glucuronides; D013267:Stilbenes; D013431:Sulfates; C499731:resveratrol-4'-O-glucuronide; D000077185:Resveratrol