1. The effect of a new rifamycin derivative, rifalazil (KRM-1648), on liver microsomal enzyme induction was studied in rat and dog with repeated oral administration of the compound. Relative liver weight, cytochrome b5 and P450 contents, enzyme activities of NADPH-cytochrome c reductase, aniline hydroxylase, p-nitroanisole O-demethylase, aminopyrine N-demethylase, and erythromycin N-demethylase were measured. 2. In rat, rifalazil treatment at 300 mg/kg/day for 10 days increased cytochrome b5 content but it did not affect liver weight, P450 content or enzyme activities. In contrast, rifampicin and rifabutin increased relative liver weights, cytochrome contents and enzyme activities under similar conditions. 3. In dog, rifalazil did not affect any parameters at 30 or 300 mg/kg/day for 13 weeks. 4. These findings indicate that rifalazil is not an enzyme inducer in rat and dog. This property differs from other rifamycin derivatives such as rifampicin and rifabutin.
The mechanism of antimicrobial activity of KRM-1648 (KRM), a new rifamycin derivative with potent antimycobacterial activity, was studied. Both KRM and rifampin (RMP) inhibited RNA polymerases from Escherichia coli and Mycobacterium avium at low concentrations: the 50% inhibitory concentrations (IC 50 s) of KRM and RMP for E. coli RNA polymerase were 0.13 and 0.10 g/ml, respectively, while the IC 50 s for M. avium RNA polymerase were 0.20 and 0.07 g/ml. Both KRM and RMP exerted weak inhibitory activity against Mycobacterium fortuitum RNA polymerase, rabbit thymus RNA polymerases, E. coli DNA polymerase I, and two types of reverse transcriptases. Uptake of 14 C-KRM by M. avium reached 18,000 dpm/mg (dry weight) 1.5 h after incubation, while uptake by E. coli cells was slight. KRM was much more effective in inhibiting uptake of 14 C-uracil than was RMP (IC 50 of KRM, 0.04 g/ml; IC 50 of RMP, 0.12 g/ml). These findings suggest, first, that the potent antimycobacterial activity of KRM is due to inhibition of bacterial RNA polymerase and, second, that the activity of KRM against target organisms depends on target cell wall permeability.3Ј-Hydroxy-5Ј-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin (KRM-1648 [KRM]), a newly synthesized rifamycin derivative, exerts much more potent in vitro and in vivo activities against slowly growing mycobacteria, including those of the Mycobacterium avium complex and Mycobacterium tuberculosis, than does rifampin (RMP) (2,9,14,17,18,22,23). Furthermore, KRM is known to exhibit potent activity in vitro and in vivo against gram-positive bacteria (3, 23) but is not effective against gram-negative bacteria or rapidly growing mycobacteria such as Mycobacterium fortuitum (3,14,23). The spectrum of activity of KRM against gram-positive and gram-negative bacteria is nearly the same as that of RMP (3). Since it is well known that the antimicrobial activity of RMP is due to inhibition of microbial DNA-dependent RNA polymerases (4,5,8,16,19,20), we studied the effects of KRM on mycobacterial RNA polymerases and its ability to permeate bacterial cells. MATERIALS AND METHODSOrganisms. M. avium, M. fortuitum, and Escherichia coli were derived from our stock cultures. The MICs of test agents for M. avium were determined with the BACTEC 460 TB system as previously described (17).Special agents. 14 C-KRM (0.51 MBq/mg) and KRM were obtained from KANEKA Corp. (Takasago, Japan). Other radiolabelled compounds were purchased from Daiichi Pure Chemical (Tokyo, Japan). Rifampin was the kind gift of Daiichi Pharmaceutical Co. (Tokyo, Japan). RNA polymerase (from E. coli) and DNA (type I from calf thymus and type VIII from E. coli) were purchased from Sigma (St. Louis, Mo.). DNA polymerase (type I from E. coli) and TTP were purchased from Takara (Kyoto, Japan). Avian myeloblastosis virus (AMV) reverse transcriptase and Moloney murine leukemia virus (MMLV) reverse transcriptase were purchased from Pharmacia Biotech (Tokyo, Japan). All other chemicals were obtained from Wako Pure Chemical Industries (Tokyo, Japa...
The pharmacokinetics of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl) benzoxazinorifamycin (KRM-1648) in rats and dogs given a single oral dose of 3, 30, or 100 mg/kg of body weight were studied. In the rats, the concentrations of KRM-1648 in plasma, whole blood, and tissues peaked between 2.0 and 24.0 h, with elimination half-lives ranging from 6.2 to 19.5 h. The peak concentrations and the areas under the concentration-versus-time curves (AUC) for whole blood and tissues were 2 to 277 times higher than those for plasma. The high levels of KRM-1648 in tissues were consistent with its large volume of distribution (in excess of 10 liters/kg). A nonlinear increase in peak concentrations and AUCs for plasma, whole blood, and tissues occurred as the dose was increased and was consistent with the dose-dependent decrease in bioavailability. In the dogs, KRM-1648 levels in plasma and whole blood also exhibited a late time to the peak concentration (ranging from 4.0 to 11.2 h), a long elimination half-life (ranging from 15.2 to 24.0 h), and nonlinear kinetics. KRM-1648 exhibited high levels of plasma protein binding (more than 99%) and a high degree of affinity for lipoproteins in the plasma of both animals. After administration of KRM-1648, measurable levels of its metabolites, 25-deacetyl KRM-1648 in rats and 25-deacetyl KRM-1648 and 30-hydroxy KRM-1648 in dogs, were found in the biological samples tested. Thus, KRM-1648 is characterized by a high tissue affinity, a long elimination half-life, and nonlinear pharmacokinetics.
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