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Pharmacokinetic/Toxicity Properties of the New Anti-Staphylococcal Lead Compound SK-03-92

1
Department of Microbiology, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA
2
Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA
3
Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53706, USA
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Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA
5
Zeeh Pharmaceutical Experiment Station, University of Wisconsin-Madison, Madison, WI 53705, USA
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Department of Chemistry and Biochemistry, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA
*
Author to whom correspondence should be addressed.
Current affiliation: FDA; US Food and Drug Administration, Office of Scientific Professional Development (OSPD), Southeast Regional Lab (SRL), 60 8th St. NE, Atlanta, GA 30309, USA
Current affiliation: Cayman Chemical Company, 1180 East Ellsworth Road, Ann Arbor, MI 48108, USA.
Academic Editor: Christopher C. Butler
Antibiotics 2015, 4(4), 617-626; https://doi.org/10.3390/antibiotics4040617
Received: 5 August 2015 / Revised: 11 November 2015 / Accepted: 18 November 2015 / Published: 24 November 2015
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 vitro against 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. View Full-Text
Keywords: Staphylococcus; pharmacokinetics; safety testing; drug formulation Staphylococcus; pharmacokinetics; safety testing; drug formulation
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Schwan, W.R.; Kolesar, J.M.; Kabir, M.S.; Elder, E.J.; Williams, J.B.; Minerath, R.; Cook, J.M.; Witzigmann, C.M.; Monte, A.; Flaherty, T. Pharmacokinetic/Toxicity Properties of the New Anti-Staphylococcal Lead Compound SK-03-92. Antibiotics 2015, 4, 617-626.

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