Short-term toxicity and observations on certain aspects of the pharmacology of a unique tetracycline-minocycline

Abstract

Minocycline was studied to determine serum or plasma drug concentrations and urinary excretion in dogs and rats following single oral or intravenous doses and to determine its short-term toxicity (1 month) in dogs by the intravenous route and in rats by gavage. Additional studies yielded information on the short-term toxicity of minocycline in the monkey and dog by the oral route of administration and on serum drug concentrations. The oral single dose study in dogs showed that at time periods up to 6 hours after dosing minocycline produced drug concentrations in the serum that were 2–3 times higher than those for tetracycline. After a single intravenous dose both compounds produced similar concentrations in the serum and showed similar magnitudes for apparent volumes of distribution and half-life. Following either route of administration, the concentrations of minocycline in the urine were considerably lower and a smaller proportion of the administered dose was recovered in the urine than with tetracycline. The administration of single daily oral doses of 30 mg/kg and two daily oral doses of 15 mg/kg for 30 days to monkeys and dogs, respectively, produced no clinical signs of toxic effects. The monkeys showed high serum drug concentrations (2–39 μg/ml) 3 hours after dosing. Concentration of 0.7 to 4.6 μg/ml were found 24 hours after dosing. Serum concentration did not appear to be cumulative although concentrations on days 4, 8, and 11 of the study were higher than concentrations on day 1. There were no drug-related changes noted in body weight and food or water intake in the dogs which received minocycline orally. High serum concentrations of drug were achieved throughout successive 24-hour periods following two daily doses of 15 mg/kg administered 8 hours apart. Serum concentrations did not appear to be cumulative although they were higher on days 15 and 29 than on day 1. Rats given minocycline by gavage daily for 1 month at doses of 8, 25, and 75 mg/kg/day were free from any clinical signs of toxic effects. Minocycline administered intravenously to dogs at doses of 5, 10, 20, and 40 mg/kg/day for 1 month produced a significant loss in body weight at the high dose level which was accompanied by a decrease in food consumption. An erythema reaction occurred at the time of drug infusion at a dose of 10 mg/kg and greater. The high dose dogs showed a slight decrease in serum protein-bound iodine values. Sulfobromophthalein retention was elevated in one and possibly in both dogs that received 40 mg/kg/day. An elevation in serum glutamic-oxalacetic and glutamic-pyruvic transaminase activities occurred in one dog which received 20 mg/kg/day. Decreases in erythrocyte packed cell volumes, hemoglobin concentrations and erythrocyte cell counts were found in all dogs that received 10 mg/kg/day or more of drug. Urinary potassium excretion was decreased slightly in five and moderately in two of eight dogs that received minocycline. A dose related effect on urinary calcium was equivocal, but was definitely increased in the high dose dogs. Tetracycline administered by the same route as a single dose of 40 mg/kg/day to two dogs produced polydipsia and polyuria as well as decreases in erythrocyte packed cell volumes, hemoglobin concentrations and erythrocyte cell counts. Glutamic-pyruvic and glutamic-oxalacetic transaminase activity increased in one dog. Both dogs showed an increase in urinary calcium excretion. Urinary potassium excretion was decreased in one dog. The one month toxicity study in dogs showed that serum antibiotic concentrations obtained with intravenously administered minocycline were approximately three time higher than those obtained with an equal dose of tetracycline. There was no evidence of systemic cumulation of microbiologically active drug. Approximately 5% of the microbiologically active minocycline was excreted in the urine compared with approximately 34% of the administered tetracycline. It is concluded from the results of these during-life studies that minocycline appears to be a drug with a good margin of safety between projected therapeutic blood concentrations and concentrations producing toxic effects.