ADSORPTION, DISPOSITION, AND METABOLISM OF TRANS-METHYL STYRYL KETONEIN FEMALE B6C3F(1) MICE

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, as we ll as consumer products. MSK does not appear to be overtly toxic in an imal models, however, it has been shown to be mutagenic in several in vitro assays after S-9 activation. In this study experiments were cond ucted to characterize MSK absorption, distribution, metabolism, and el imination after iv, oral, and topical administration to female B6C3F(1 ) mice. After iv administration, [C-14]MSK (20 mg/kg; 120 mu Ci/kg) wa s rapidly cleared from the blood as evidenced by the following pharmac okinetic values (mean +/- SD): terminal disposition half-life (t(1/2), 7.98 +/- 1.72 min; mean residence time, 5.6 +/- 1.7 min; steady-state apparent volume of distribution (V-ss), 3.33 +/- 0.75 liters/kg; and systemic body clearance (CLs), 0.53 +/- 0.05 liters/min/kg. Within 48 hr, 92.4% of the dose was excreted in the urine and 3.5% in the feces. The major blood metabolites after iv administration were identified b y GC-MS as the 4-phenyl-3-buten-2-ol (methyl styryl carbinol), 4-hydro xy-4-phenyl-2-butanone, and benzyl alcohol. After oral administration of [C-14]MSK (200 mg/kg; 100 mu Ci/kg), 95% of the dosed radioactivity was recovered in the urine and 1.2% in the feces within 48 hr. Major urinary metabolites were identified by LC-MS/MS as N-phenylacetyl-1-gl ycine (35.1% of dose) and N-benzyl-L-glycine (19.1% of dose). Only a s mall amount of MSK was detected in the blood after oral administration (similar to 0.73 mu g/ml at 10 min), and [C-14]-equivalents in the bl ood never exceeded 2.8% of the dose. Ater topical application of [C-14 ]MSK (250 mg/kg; 50 mu Ci/kg), approximately 40% of the dose was absor bed and 84.5% of the absorbed dose was excreted into the urine (36% of the total dose). Urinary metabolites were similar to those described for oral administration. Importantly, [C-14]-equivalents were not dete cted in the blood at any time after dermal administration. These resul ts indicate that the rate of MSK clearance is equivalent to its rate o f absorption, and tissue exposure to intact MSK is expected to be limi ted.