ORAL AND TOPICAL ABSORPTION, DISPOSITION KINETICS, AND THE METABOLIC-FATE OF TRANS-METHYL STYRYL KETONE IN THE MALE FISCHER-344 RAT

trans-Methyl styryl ketone (MSK; trans-4-phenyl-3-buten-2-one) is a be ta-unsaturated ketone that has a wide range of uses in industry and is present in numerous consumer products, Although MSK has been shown to be positive in several in vitro mutagenic assays, it does not seem to be overtly toxic in animal models, This lack of toxicity may relate t o its poor absorption and/or rapid elimination, However, little is kno wn about the fate of MSK in the body, Studies were conducted to charac terize the absorption, and disposition kinetics of MSK after intraveno us, oral, and topical administration to male Fischer 344 rats, After i ntravenous administration of [C-14]MSK (20 mg/kg, 120 mu Ci/kg), blood concentration-time data could be characterized with a biexponential e quation and apparent first-order elimination kinetics, The following p harmacokinetic parameter values were obtained (mean +/- SD): terminal disposition half-life, 17.7 +/- 0.08 min; apparent steady-state volume of distribution, 0.89 +/- 0.14 liters/kg; systemic body clearance, 68 .9 +/- 10.0 ml/kg min; and mean residence time, 13.1 +/- 2.2 min, Wi thin 48 hr, 95.5% of the dose was excreted in the urine and 2.7% in th e feces, The major blood metabolite after intravenous administration w as identified by GC/MS as the 4-phenyl-3-buten-2-ol (methyl styryl) ca rbinol), After oral administration of [C-14]MSK (200 mg/kg, 100 mu Ci/ kg), similar to 96.6% of the dosed radioactivity was recovered in the urine and 4.8% in the feces within 48 hr, Major urinary metabolites id entified by LC-MS/MS and quantified by HPLC radioassay were N-phenylac etyl-L-glycine (64.9% of dose) and N-benzyl-L-glycine (9.9% of dose), Parent compound could not be detected in the blood after oral administ ration, and C-14-equivalents in the blood never exceeded 1.3% of the d ose, Results suggest near-total pre-systemic elimination of the oral d ose, After topical application of [C-14]MSK (250 mg/kg, 50 mu Ci/kg), >60% of the dose was absorbed, and the majority of the dose was excret ed into the urine (55% of dose) in the form of metabolites, Urinary me tabolites were similar to those described after oral administration. C -14-equivalents were not detected in the blood at any time after topic al administration. These results indicate that MSK is almost totally m etabolized before systemic distribution after oral or topical administ ration. The systemic exposure dose of MSK seems to be exceedingly low at the doses studied herein.