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Enhancement by a high fat meal of the absorption of orally administered T2000 (1,3‐bismethoxymethyl‐5,5‐diphenylbarbituric acid; I) in man
Author(s) -
Raines Arthur,
Ganes Derek,
Levitt Barrie,
Moros Daniel,
LeBel Marc,
Rutman Howard,
Yacobi Avraham
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a416-d
Subject(s) - cmax , meal , absorption (acoustics) , chemistry , pharmacokinetics , bioavailability , oral administration , medicine , zoology , pharmacology , biology , physics , acoustics
I is presently under evaluation for potential utility in essential tremor and seizure disorders. The compound lacks prominent sedative‐hypnotic activity usually associated with this chemical class of drugs. I is biotransformed to monomethoxymethyl‐5,5‐diphenylbarbituric acid (II) and to 5,5‐diphenylbarbituric acid (III) in the rat, dog and man. II and III appear to be active metabolites. I has limited aqueous solubility; in an effort to enhance absorption from the gastrointestinal tract, we evaluated the influence of a high fat breakfast on gastrointestinal absorption of I in 23 healthy non‐smoking male volunteers between 19 and 54 years of age. The rate and extent of absorption was assessed by measuring the plasma levels of I, II and III over the course of 5 days after an oral dose of 400 mg of I. Results: The mean ratios for C max (fed/fasting) for I, II and III were 6.88, 3.14 and 1.59, respectively. Mean t max ratios (fed/fasting) for the 3 compounds were 0.65, 0.44 and 0.88 for I, II and III. Mean ratios for AUC 0‐t (fed/fasting) for I, II and III were 2.81, 2.74 and 1.53, respectively. Mean terminal half‐lives for I, II and III ranged between 18‐26, 16‐27 and 39‐43 hours, respectively. Conclusion: A high fat meal enhances the oral absorption of T2000 in man as indicated by higher C max , earlier t max and greater AUC after a high fat breakfast than in the fasting state. As expected, terminal half‐lives of all 3 compounds did not change.