Pharmacokinetic/Toxicity Properties of the New Anti-Staphylococcal Lead Compound SK-03-92
| Autor: | Edmund J. Elder, Rachel Minerath, Christopher M. Witzigmann, James M. Cook, Jeffrey B. Williams, Aaron Monte, William R. Schwan, M. Shahjahan Kabir, Jill M. Kolesar, Tricia Flaherty |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Microbiology (medical)
Drug media_common.quotation_subject Staphylococcus Pharmacology Pharmaceutical formulation Biochemistry Microbiology chemistry.chemical_compound Pharmacokinetics safety testing Pharmacology (medical) General Pharmacology Toxicology and Pharmaceutics Adverse effect IC50 media_common Communication lcsh:RM1-950 3. Good health Bioavailability drug formulation Infectious Diseases lcsh:Therapeutics. Pharmacology chemistry Toxicity Lead compound pharmacokinetics |
| Zdroj: | Antibiotics, Vol 4, Iss 4, Pp 617-626 (2015) Antibiotics |
| ISSN: | 2079-6382 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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