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Antibiotics 2015, 4(4), 617-626; doi:10.3390/antibiotics4040617

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
4
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
6
Department of Chemistry and Biochemistry, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA
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.
*
Author to whom correspondence should be addressed.
Academic Editor: Christopher C. Butler
Received: 5 August 2015 / Revised: 11 November 2015 / Accepted: 18 November 2015 / Published: 24 November 2015
View Full-Text   |   Download PDF [684 KB, uploaded 24 November 2015]   |  

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 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
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

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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