Wallace W. Bradford

Glucuronidation of trans‐resveratrol by human liver and intestinal microsomes and UGT isoforms

Resveratrol (trans‐resveratrol, trans‐3,5,4′‐trihydroxystilbene) is a naturally occurring stilbene analogue found in high concentrations in red wine. There is considerable research interest to determine the therapeutic potential of resveratrol, as it has been shown to have tumour inhibitory and antioxidant properties. This study was performed to investigate the glucuronidation of resveratrol and possible drug interactions via glucuronidation. Two glucuronide conjugates, resveratrol 3‐O‐glucuronide and resveratrol 4′‐O‐glucuronide, were formed by human liver and intestinal microsomes. UGT1A1 and UGT1A9 were predominantly responsible for the formation of the 3‐O‐glucuronide (Km = 149 μm) and 4′‐O‐glucuronide (Km = 365 μm), respectively. The glucuronide conjugates were formed at higher levels (up to 10‐fold) by intestinal rather than liver microsomes. Resveratrol was co‐incubated with substrates of UGT1A1 (bilirubin and 7‐ethyl‐10‐hydroxycamptothecin (SN‐38)) and UGT1A9 (7‐hydroxytrifluoromethyl coumarin (7‐HFC)). No major changes were noted in bilirubin glucuronidation in the presence of resveratrol. Resveratrol significantly inhibited the glucuronidation of SN‐38 (Ki = 6.2 ± 2.1 μm) and 7‐HFC (Ki = 0.6 ± 0.2 μm). Hence, resveratrol has the potential to inhibit the glucuronidation of concomitantly administered therapeutic drugs or dietary components that are substrates of UGT1A1 and UGT1A9.

Synthesis of acyclonucleoside phosphonates as antiviral agents against cytomegalovirus

Abstract Phosphonic acid analogs of ACV and DHPG that are isosteric with ACV phosphate and DHPG phosphate have been synthesized and evaluated for antiviral activity against human, murine, and guinea pig strains of cytomegalovirus. The phosphonates showed high activity against all of the strains. They were also evaluated against a DHPG resistant strain of human cytomegalovirus. Although the activity dropped considerably, significant antiviral activity was still evident.

Combined chromatographic—isotopic dilution analysis of fecapentaenes in human feces

Fecapentaene-12 (FP-12) and fecapentaene-14 (FP-14) are genotoxic unsaturated ether lipids produced by colonic bacteria in man. We have developed and applied to feces collections from normal volunteers direct isotopic dilution procedures using tritium-labeled (at C5) FP-12 and FP-14 for measuring these compounds. FPs were recovered from feces by solvent extraction, silica cartridge clean-up, and analytical liquid chromatography. Low levels of FP-12 and FP-14 (less than 0.1 to 2.4 micrograms/g of freeze-dried feces) were observed. Identity of chromatographic peaks was established by co-elution and by ultraviolet absorption spectra obtained via photodiode array scanning. Two unknown peaks were tentatively identified from absorption spectra as closely related compounds with increased (hexane?) or decreased (tetraene?) number of double bonds. Levels of FPs increased after incubation of feces at 37 degrees C for 96 h under anaerobic conditions and pre-FP-12 and pre-FP-14 peaks were observed, which showed identical spectra with authentic FPs. These were interpreted to be isomeric forms of the all-trans-[3H]FPs used for the isotopic dilution analysis. Total FPs (including pre-FP) yielded a range of 0.3-80 micrograms FP-12 and 2.8-44 micrograms FP-14 per g of freeze-dried feces from the study group.

Carbon-14 labeling of K777•HCl, a therapeutic agent for Chagas disease.

The antitrypanosomal agent K777•HCl was labeled with carbon-14 to support absorption, distribution, metabolism, and excretion studies of this potential new drug for the treatment of Chagas disease. The radiolabeled compound was prepared in eight steps from [(14) C(U)]-(l)-phenylalanine with a specific activity of 54.4 mCi/mmol and an overall radiochemical yield of 4.1%.