A single dose of Polymyxin B, 5 mg/kg, or Compound 48/80, 3 mg/kg, increases the skeletal muscle-type creatine phosphokinase (PCPK) activity in rat plasma.3 After a 1- to 3-day period of daily treatments with increasing doses of Polymyxin B or Compound 48/80, the same doses of Polymyxin B or Compound 48/80, i.p., as cited above produce markedly smaller or no increases in PCPK, plasma aspartate aminotransferase (GOT) or plasma lactic dehydrogenase activities. However, administration of Polymyxin B, 10 mg/kg, i.p., or Compound 48/80, 6 mg/kg, i.p., on the day after completion of the 3-day pretreatment with the same drug did produce increased PCPK activities. The increase in PCPK activity produced by Polymyxin B, 5 mg/kg, or Compound 48/80, 3 mg/kg, was significantly smaller in rats pretreated with Compound 48/80 or Polymyxin B, respectively, for 3 days, than in naive rats. Ten days after completing the 3-day Polymyxin B pretreatment, Polymyxin B, 5 mg/kg, produced an increase in PCPK activities. The increases in PCPK activity produced by restraint stress or other pharmacological agents were not diminished by prior treatment with Polymyxin B for 3 days. The evidence suggests that tolerance to the toxic effects of Polymyxin B or Compound 48/80 on skeletal muscle and other tissues develop with two or more doses of Polymyxin B or Compound 48/80.
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