Abstract
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.
Footnotes
This work was supported in part by the National Institutes of Health National Cancer Institute [Grants R03-CA133943, R03-CA159389].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- MIST
- drug metabolites in safety testing
- PK
- pharmacokinetics
- R3S
- trans-resveratrol-3-sulfate
- R3G
- trans-resveratrol-3-O-glucuronide
- RES
- trans-3,5,4′-trihydroxystilbene
- R4′G
- trans-resveratrol-4′-O-glucuronide
- R4′S
- trans-resveratrol-4′-sulfate
- i.a.
- intra-arterial administration
- AUC
- area under the plasma concentration-time curve
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- APAP
- acetaminophen
- IS
- internal standard
- LOQ
- limit of quantitation
- MRT
- mean residence time
- Cl
- clearance
- CV
- coefficient of variation.
- Received April 23, 2012.
- Accepted July 17, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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