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

• Main Authors: William R. Schwan (Author), Jill M. Kolesar (Author), M. Shahjahan Kabir (Author), Edmund J. Elder (Author), Jeffrey B. Williams (Author), Rachel Minerath (Author), James M. Cook (Author), Christopher M. Witzigmann (Author), Aaron Monte (Author), Tricia Flaherty (Author)
• Format: Book
• Published: MDPI AG, 2015-11-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2079-6382; 10.3390/antibiotics4040617
• Keywords: Staphylococcus; pharmacokinetics; safety testing; drug formulation; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 4, Iss 4, Pp 617-626 (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.