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

Antibiotics

William R. Schwan²  Jill M. Kolesar⁵  M. Shahjahan Kabir¹  Edmund J. Elder³  Jeffrey B. Williams³  Rachel Minerath²  James M. Cook¹  Christopher M. Witzigmann¹  Aaron Monte⁴  Tricia Flaherty² 

[1] Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA; E-Mails:;Department of Microbiology, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA; E-Mails:;Zeeh Pharmaceutical Experiment Station, University of Wisconsin-Madison, Madison, WI 53705, USA; E-Mails:;Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, 1725 State St., La Crosse, WI 54601, USA; E-Mail:;Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, WI 53706, USA; E-Mail:

关键词: Staphylococcus;    pharmacokinetics;    safety testing;    drug formulation;   

DOI  :  10.3390/antibiotics4040617

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.