Abstract
trans-Methyl styryl ketone (MSK;trans-4-phenyl-3-buten-2-one) is a β-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 (t½), 7.98 ± 1.72 min; mean residence time, 5.6 ± 1.7 min; steady-state apparent volume of distribution (Vss), 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 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.
Footnotes
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Send reprint requests to: Dr. I. Glenn Sipes, Department of Pharmacology and Toxicology, College of Pharmacy, P.O. Box 210207, The University of Arizona, Tucson, AZ 85721-0207. E-mail:Sipes{at}pharmacy.arizona.edu.
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This research was supported by a contract from NIEHS (ES-35367) and the NIEHS-sponsored Southwest Environmental Health Sciences Center (P30-ES-06694). John-Michael Sauer was supported in part by a Graduate Training Program in Environmental Toxicology Fellowship (T32-ES-07091–17).
- Abbreviations used are::
- MSK
- trans-methyl styryl ketone
- HPLC
- high pressure liquid chromatography
- Received April 25, 1997.
- Accepted June 23, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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