title: Antimycobacterial activities in vitro and in vivo and pharmacokinetics of dihydromycoplanecin A.
abstract: The in vitro activity of dihydromycoplanecin A (DHMP A), a new cyclic peptide antibiotic, was compared with those of antimycobacterial drugs such as streptomycin, isoniazid (INH), rifampin, and ofloxacin against several clinically isolated species of mycobacteria, including Mycobacterium tuberculosis, M. intracellulare, and M. kansasii. DHMP A demonstrated stronger activities than other drugs against all species of mycobacteria tested at concentrations of less than 0.0125 to 25 microgram/ml. A marked synergism between DHMP A and INH was demonstrated by the checkerboard technique against M. tuberculosis, M. intracellulare, and M. smegmatis, and the synergistic effect was observed by treatment of the culture of M. smegmatis with DHMP A for at least 3 h prior to treatment with INH. It was also shown that both absorption and excretion of INH in mice were faster than those of DHMP A. On the basis of these results, combination therapy with DHMP A and INH was successfully carried out in experimental tuberculosis in mice infected with M. bovis Ravenel. After a single intravenous administration of 10 mg of DHMP A per kg, its half-life in serum in mice was about 0.5 h and in dogs it was 5.5 h. A single oral administration to dogs of 12.5 mg/kg gave a peak of 5.0 micrograms/ml at 3 h. In these experiments, urinary recoveries within 48 h were 21.0% in mice and 25.2% in dogs. The tissue distribution level of DHMP A in mice after oral administration was in the order of liver greater than kidney greater than serum greater than spleen = lung. The 50% lethal doses of DHMP A for mice were more than 6,000 mg/kg orally and 1,840 mg/kg intraperitoneally.
authors.affiliation: Fermentation Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Haneishi
authors.forename: M
authors.initials: M
authors.lastname: Nakajima
authors.forename: A
authors.initials: A
authors.lastname: Shiraishi
authors.forename: T
authors.initials: T
authors.lastname: Katayama
authors.forename: A
authors.initials: A
authors.lastname: Torikata
authors.forename: Y
authors.initials: Y
authors.lastname: Kawahara
authors.forename: K
authors.initials: K
authors.lastname: Kurihara
authors.forename: M
authors.initials: M
authors.lastname: Arai
authors.forename: T
authors.initials: T
authors.lastname: Arai
authors.forename: T
authors.initials: T
authors.lastname: Aoyagi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D023181:Antimicrobial Cationic Peptides; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D007275:Injections, Intravenous; D007538:Isoniazid / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009161:Mycobacterium / Q000187:drug effects*; D009164:Mycobacterium Infections / Q000188:drug therapy; D010455:Peptides; D010456:Peptides, Cyclic / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D051381:Rats; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D010455:Peptides; D010456:Peptides, Cyclic; C055186:dihydromycoplanecin A; D007538:Isoniazid