title: Pharmacokinetic/Toxicity Properties of the New Anti-Staphylococcal Lead Compound SK-03-92.
abstract: Because of the potential of a new anti-staphylococcal lead compound SK-03-92 as a topical antibiotic, a patch, or an orally active drug, we sought to determine its safety profile and oral bioavailability. SK-03-92 had a high IC50(125 μg/ml)in vitroagainst several mammalian cell lines, and mice injected intraperiteonally at the highest dose did not exhibit gross toxicity (e.g.altered gait, ungroomed, significant weight loss). Single dose (100 μg/g) pharmacokinetic (PK) analysis with formulated SK-03-92 showed that peak plasma concentration (1.64 μg/ml) was achieved at 20-30 min. Oral relative bioavailability was 8%, and the drug half-life was 20-30 min, demonstrating that SK-03-92 is likely not a candidate for oral delivery. Five-day and two-week PK analyses demonstrated that SK-03-92 plasma levels were low. Multi-dose analysis showed no gross adverse effects to the mice and a SK-03-92 peak plasma concentration of 2.12 μg/ml with the presence of significant concentrations of breakdown products 15 min after dosing. SK-03-92 appeared to be very safe based on tissue culture and mouse gross toxicity determinations, but the peak plasma concentration suggests that a pro-drug of SK-03-92 or preparation of analogs of SK-03-92 with greater bioavailability and longer half-lives are warranted.
authors.affiliation: Department of Microbiology, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA; Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Schwan
authors.affiliation: Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kolesar
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA.
authors.forename: M Shahjahan
authors.initials: MS
authors.lastname: Kabir
authors.affiliation: Zeeh Pharmaceutical Experiment Station, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Elder
authors.affiliation: Zeeh Pharmaceutical Experiment Station, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Williams
authors.affiliation: Department of Microbiology, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Minerath
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Witzigmann
authors.affiliation: Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA; Department of Chemistry and Biochemistry, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Monte
authors.affiliation: Department of Microbiology, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA.
authors.forename: Tricia
authors.initials: T
authors.lastname: Flaherty
keywords: Staphylococcus; drug formulation; pharmacokinetics; safety testing