Toxicity, bioavailability and pharmacokinetics of a newly formulated colistin sulfate solution.
We formulated a new colistin sulfate injectable solution and tested its effectiveness, toxicity and pharmacokinetics in vivo on mice, rabbits, and piglets. When intramuscularly injected (i.m.) into rabbits at 0.5 mL per site, the 2.5% colistin sulfate solution caused no reaction at the injection site, but the 5.0% solution caused the muscle circumference to appear erythematic. Tested LD50 in CD-1 mice were 38.72 mg/kg for i.m. and 431.95 mg/kg for oral administration, respectively. At 15.0 mg/kg/day (i.m.) for 5 days, colistin sulfate caused obvious neurotoxicity to piglets with moderate granular degenerations in the epithelial tissues from kidney and liver. These toxic responses were not seen when colistin sulfate was injected at 10.0 mg/kg/day for 5 days. Pharmacokinetic studies revealed Cmax of 3.73 +/- 0.28 and 6.40 +/- 0.18 microg/mL, Tmax of 32 +/- 1.5 and 34 +/- 1.8 min, t(1/2beta) of 256 +/- 14 and 264 +/- 29 min, and absolute bioavailability of 95.94 and 88.45% for colistin sulfate intramuscularly injected to piglets at 2.5 and 5.0 mg/kg, respectively. Serum colistin sulfate concentration followed a two-compartment open model showing first-order absorption. The high bioavailability and the long-lasting serum retention time indicated that the new solution is suitable for i.m. in piglets with a recommended dose of 2.5 mg/kg injected twice daily.
Lin
B
B
Division of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing, China.
Zhang
C
C
Xiao
X
X
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood; D001682:Biological Availability; D001774:Blood Chemical Analysis / Q000662:veterinary; D002626:Chemistry, Pharmaceutical; D003091:Colistin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D007273:Injections, Intramuscular / Q000662:veterinary; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000097:blood; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice / Q000378:metabolism; D011817:Rabbits / Q000378:metabolism; D013552:Swine / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000097:blood
D000900:Anti-Bacterial Agents; D007770:L-Lactate Dehydrogenase; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D003091:Colistin