0090-9556/97/2510-1184-1190$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 10

ARTICLE
Absorption, Disposition, and Metabolism of trans-Methyl Styryl Ketone in Female B6C3F₁ Mice

John-Michael Sauer, Jingqi Bao, Richard L. Smith, Robert K. Kuester, Michael Mayersohn, and I. Glenn Sipes

Department of Pharmacology and Toxicology and Center for Toxicology, The University of Arizona

trans-Methyl styryl ketone (MSK; trans-4-phenyl-3-buten-2-one) is a -unsaturated ketone that has a wide range of uses in industry, as well as consumer products. MSK does not appear to be overtly toxic in animal models, however, it has been shown to be mutagenic in several in vitro assays after S-9 activation. In this study experiments were conducted to characterize MSK absorption, distribution, metabolism, and elimination after iv, oral, and topical administration to female B6C3F₁ mice. After iv administration, [¹⁴C]MSK (20 mg/kg; 120 µCi/kg) was rapidly cleared from the blood as evidenced by the following pharmacokinetic 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 (CL_s), 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 by GC-MS as the 4-phenyl-3-buten-2-ol (methyl styryl carbinol), 4-hydroxy-4-phenyl-2-butanone, and benzyl alcohol. After oral administration of [¹⁴C]MSK (200 mg/kg; 100 µCi/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-l-glycine (35.1% of dose) and N-benzyl-L-glycine (19.1% of dose). Only a small amount of MSK was detected in the blood after oral administration (~0.73 µg/ml at 10 min), and [¹⁴C]-equivalents in the blood never exceeded 2.8% of the dose. Ater topical application of [¹⁴C]MSK (250 mg/kg; 50 µCi/kg), approximately 40% of the dose was absorbed 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, [¹⁴C]-equivalents were not detected in the blood at any time after dermal administration. These results indicate that the rate of MSK clearance is equivalent to its rate of absorption, and tissue exposure to intact MSK is expected to be limited.