Takeshi Fugono

Comparative pharmacokinetics of carumonam and aztreonam in mice, rats, rabbits, dogs, and cynomolgus monkeys.

The pharmacokinetic properties of carumonam (AMA-1080, Ro 17-2301) were studied in mice, rats, rabbits, dogs, and cynomolgus monkeys and compared with those of aztreonam. Carumonam administered subcutaneously in mice or intramuscularly in rats, rabbits, dogs, and cynomolgus monkeys at a dose of 20 mg/kg was readily absorbed and distributed at high concentrations in the plasma, kidneys, liver, and lungs, as was aztreonam. The peak level of carumonam in plasma, ranging from 41 micrograms/ml in mice to 68 micrograms/ml in monkeys; the area under the plasma concentration-time curve, ranging from 20 micrograms X h/ml in mice to 80 micrograms X h/ml in monkeys; the plasma half-life, ranging from 0.24 h in mice to 1.10 h in dogs; and the plasma clearance, ranging from 4.5 ml/min per kg in monkeys to 16.7 ml/min per kg in mice, resembled respective values of aztreonam. In rats, carumonam was eliminated faster than aztreonam. The levels of both antibiotics in the kidneys and liver were usually higher than respective levels in plasma. The level of carumonam in the kidney was usually higher than that of aztreonam, whereas the level of aztreonam in the liver was usually higher than that of carumonam. Both antibiotics showed similar distribution in the lung and spleen; the levels in these tissues were less than the levels in plasma. Carumonam was excreted mainly in the urine; the recovery ranged from 52% (from dogs) to 73% (from rabbits). The urinary recovery of carumonam from mice, rats, and monkeys was higher, but the recovery of carumonam from rabbits and dogs was lower than that of aztreonam. The biliary excretion of carumonam, amounting to 4.1% from rats and less than 0.3% from rabbits and dogs, was smaller than that of aztreonam, amounting to 19.1% from rats and around 1% from rabbits and dogs. The extent of protein binding at 20 micrograms of carumonam per ml was lower than that of aztreonam. For all species except dogs, which have very low binding in their serum (11% for carumonam and 20% for aztreonam), the binding of carumonam ranged from 21% (in rabbits) to 36% (in rats), whereas that of aztreonam ranged from 55% (in rabbits) to 85% (in rats). Thus, the plasma pharmacokinetics of carumonam and aztreonam were generally similar for all animals tested except dogs, but the two antibiotics differed slightly in their distribution in tissue, excretion, and protein binding in serum.

Chemical Modification of Maridomycin, a New Macrolide Antibiotic

Maridomycin, a new macrolide antibiotic, and tetrahydromaridomycin were acylated into their mono, di, and tri acyl derivatives. These derivatives were compared with the parent antibiotic, maridomycin, for their (i) in vitro antimicrobial activities, (ii) protective effect in mice infected with Staphylococcus aureus (oral administration), (iii) blood levels attained in rats, and (iv) acute toxicity in mice (intraperitoneal administration). All the derivatives showed either the same or less activity in vitro, but 9-acyl, 9, 2′-diacylmaridomycin and 9, 13, 2′-triacetyltetrahydromaridomycin demonstrated improved therapeutic effects together with higher blood levels and low toxicity. 9-Propionylmaridomycin showed the most favorable biological properties. Images

The Metabolic Fate of α-Sulphobenzylpenicillin in Rats

1. After intramuscular injection of a new semi-synthetic penicillin, disodium [14C]α-sulphobenzylpenicillin, to rats radioactivity in blood reached a peak at 5 min with a half life of 26 min. Most of the blood radioactivity was not bound to plasma protein and 70% was accounted for as the intact penicillin.2. At 20 min after dosage the radioactivity was distributed mostly in liver, kidney, intestinal contents and blood. About half of the injected radioactivity was excreted into the urine within 8 h. Faecal excretion was much slower but continued for longer duration and amounted to 24% after 3 days.3. In bile-duct cannulated rats, 35% of the dosed radioactivity was excreted into bile and 52% into urine within 24 h.4. In both urine and bile, 50 to 85% of the radioactivity was present as unchanged drug and 10 to 20% as its penicilloic acid.5. Intravenous injection gave similar metabolic patterns as those observed after intramuscular injection except that faecal excretion was increased.6. Autoradiographic stud...

ENDURACIDIN, A NEW ANTIBIOTIC. IV

A rapid mobilization of enduracidin, introduced into the circulation, to each tissue was suggested from the results of intravenous injection and constant infusion studies in which blood levels and excretion into urine and bile were observed. Following intramuscular injection of 2 mg/kg of enduracidin, a plateau in the blood level (approximately 4 mcg/ml) was reached at 2 hours after the injection and this persisted for the next 2 hours and then decreased gradually. Increase in the dose resulted in the prolongation of the plateau, rather than a further rise in the maximum blood level. Except for the brain, enduracidin was found to distribute widely in the tissues including heart, lung, liver, spleen, adrenal, kidney, testis and muscle. Among these tissues, lung, liver, spleen and kidney contained higher concentrations of enduracidin than others, and in the case of multiple daily intramuscular injections, a parallel was noted in tissue enduracidin levels with doses and number of injections, with the exception of kidney. Enduracidin, once transported to the tissues, was retained for rather long period of time in the liver, and except for the kidney, presumably in other tissues. Enduracidin may be excreted mainly via urinary excretion.