Uptake and metabolism of BuCast: a glycoprotein processing inhibitor and a potential anti-HIV drug |
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Authors: | Kang Mohinder S |
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Institution: | Hoechst Marion Roussel Inc. 2110 East Galbraith Road, Cincinnati, OH 45215. USA |
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Abstract: | We have previously shown (Sunkara et al., 1989; Taylor et al.,1991) that 6-o-butanoyl castanospermine (BuCast) was a 3050-foldbetter inhibitor of HIV syncytia formalion than castanospermine(Cast). Radiolabeled Cast and BuCast were used to study theuptake and metabolism of these compounds in cultured cells andin mice. BuCast was preferentially taken up by cells comparedto Cast. Approximately 3050-fold higher radioactivitywas found in cells treated with BuCast compared to cells treatedwith Cast during the initial 46h of labeling. HPLC analysisshowed that once BuCast was taken up by cells, it was rapidlyconverted to Cast. Mice given oral doses of BuCast had 510-foldhigher levels of Cast in the plasma and tissues as comparedto Cast treated mice. However, when the compounds were giveni.v., the levels of plasma and tissue radioactivity obtainedfrom Cast or BuCast were equivalent suggesting rapid conversionof BuCast to Cast in the blood. In mice orally treated withBuCast, HPLC analysis suggested that only Cast was found inthe plasma and tissues. With multiple dosing of mice, additiveresults were obtained, suggesting that multiple doses may beused to obtain higher concentrations of the compound in thetarget cells. These data suggest that the lipophilic propertiesof butanoyl side chain on the Cast ring makes BuCast significantlybetter absorbed, and this may help to alleviate some of thegut toxicity associated with Cast treatment. HIV AIDS glycoproteins inhibitors |
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