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 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 to its poor absorption and/or rapid elimination. However, little is known about the fate of MSK in the body. Studies were conducted to characterize the absorption, and disposition kinetics of MSK after intravenous, oral, and topical administration to male Fischer 344 rats. After intravenous administration of [14C]MSK (20 mg/kg, 120 μCi/kg), blood concentration-time data could be characterized with a biexponential equation and apparent first-order elimination kinetics. The following pharmacokinetic 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. Within 48 hr, 95.5% of the dose was excreted in the urine and 2.7% in the feces. The major blood metabolite after intravenous administration was identified by GC/MS as the 4-phenyl-3-buten-2-ol (methyl styryl carbinol). After oral administration of [14C]MSK (200 mg/kg, 100 μCi/kg), ∼96.6% of the dosed radioactivity was recovered in the urine and 4.8% in the feces within 48 hr. Major urinary metabolites identified by LC-MS/MS and quantified by HPLC radioassay wereN-phenylacetyl-l-glycine (64.9% of dose) andN-benzyl-l-glycine (9.9% of dose). Parent compound could not be detected in the blood after oral administration, and 14C-equivalents in the blood never exceeded 1.3% of the dose. Results suggest near-total presystemic elimination of the oral dose. After topical application of [14C]MSK (250 mg/kg, 50 μCi/kg), >60% of the dose was absorbed, and the majority of the dose was excreted into the urine (55% of dose) in the form of metabolites. Urinary metabolites were similar to those described after oral administration. 14C-equivalents were not detected in the blood at any time after topical administration. These results indicate that MSK is almost totally metabolized before systemic distribution after oral or topical administration. The systemic exposure dose of MSK seems to be exceedingly low at the doses studied herein.
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.
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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). J.-M.S. 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
- JVC
- jugular vein cannulation
- CLS
- systemic clearance
- VSS
- steady-state volume of distribution
- ty2
- terminal half-life
- MRT
- mean residence time
- AUC
- area under the plasma concentration-time curve
- AUMC
- area under the first moment of the plasma concentration-time curve
- DCM
- dichloromethane
- CID
- collision-induced dissociation
- EI
- electron impact
- NIEHS
- National Institute of Environmental Health Sciences
- Received December 16, 1996.
- Accepted March 10, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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