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Tributyrin (TB) is detectable as free drug in plasma after oral administration

Sub-category: Pharmacokinetics
Category: Clinical Pharmacology
Meeting: 2002 ASCO Annual Meeting

Abstract No: 2174
Citation: Proc Am Soc Clin Oncol 21: 2002 (abstr 2174)
Author(s): Shyam L Khanwani, Martin J Edelman, Ken Bauer, Noble Nemieboka, Judith Karp, University of Maryland Cancer Center, Baltimore, MD.

Abstract: Introduction: Butyrate (B) is a small polar compound able to alter gene expression and induce apoptosis and terminal differentiation in vitro. Concentrations necessary to achieve these results are between 500-3000 uM. TB is an orally available B prodrug which was previously thought to be completely hydrolyzed in the intestine to B. We have reported that levels of B associated with in-vitro activity are achievable after po administration of TB (PASCO 20:86a 2001). We now report that TB is also present as intact drug in plasma.

Method: TB plasma concentrations were measured using gas chromatography with flame ionization detection. Patient plasma samples of 100 uL were extracted with 100% ethanol and reconstituted with 50 uL of acetonitrile for analysis. Plasma samples from a total of 11 patients receiving 200 mg/m2 TID were analyzed. Pharmacokinetic samples were obtained on Days 1, 2, 15, and 16.

Results: We were able to detect TB in 4 of 11 patients. TB concentrations in these patients ranged from 0.3 to 2.0 ug/mL. Two patients had detectable levels on day 1 and on additional days. Two other patients had detectable levels on either Day 2, 15, or 16 thereafter.

Conclusion: Based upon these results we conclude that not all orally administered TB is hydrolyzed to B. This may be clinically significant as TB is more active than B in vitro. We plan to further explore the pharmacokinetics of TB in Phase II studies. Supported by U01 CA 69854