Rifamycins rifampicins

Figure 3.6 Comparison of the chemical structures of rifamycin (Rifampicin ) and rifamycin CGP 4832 the latter is transported by FhuA. Note the entirely different chemical structures (Figure 3.2) and conformations (Figure 3.5) of the ferrichrome and albomycin FhuA transport substrates.

Rifapentine (DL473) [61379-65-5] (40), C42H34N4O22, a pipera2inyl hydra2one of 3-formyl rifamycin SV, is similar to rifampicin. Rifapentine has activity similar to rifampicin, but its half-life is much longer (149,150). 

Rifampicin, the only commercially available ansamacroHde, is manufactured by MerreU Dow under the tradename Rifadin, and by CIBA under the trade name Rimactane. Rifampicin is also suppHed in combination with isoniazid or pyrazinamide [98-96-4]. The rifampicin—isoniazid combination is known as Rifamate (MerreU Dow), Rifinah (MerreU Dow), and Rimactazid (CIBA) the rifampicin—pyrazinamide as Rifater (MerreU Dow). Several other rifamycin derivatives including rifabutin and rifapentine are undergoing clinical studies. 

Common Name 3-[(4-Methyl-1 -piperazinyDiminomethyl] rifamycin SV rifaldazine rifa-mycin AMF rifampicin... 

As far as sinusoidal uptake is concerned, drug-drug interactions have also been reported between antituberculosis agents (rifamycin SV and rifampicin) and bromosulfophthalein in humans both drugs reduce the clearance of bromosul-fophthalein and also induce hyperbilirubinemia [108]. These results may be ac-... 

K., Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver, Hepatology... 

Fig. 2. Chemical structures of rifampicin and rifaximin as well as of their parent compound, rifamycin SV. The empirical formula of rifaximin is C43H51N3O11 and its molecular weight 785.9 daltons.

To establish whether rifaximin, like the other members of the rifamycin family [36, 58], specifically inhibits bacterial RNA synthesis the effect of this antibiotic as well as that of rifampicin and chloramphenicol on RNA (via 3H-uridine incorporation), DNA (via 3H-thymidine incorporation) and protein (via 35S-methionine incorporation) synthesis was studied in growing cultures of Escherichia coli [59], While chloramphenicol reduced protein synthesis, both rifaximin and rifampicin inhibited RNA synthesis in a concentration-dependent fashion. In contrast, none of them affected 3H-thymidine incorporation into DNA. These data suggest that rifaximin, like rifampicin, inhibits RNA synthesis by binding the (3 subunit of the bacterial DNA-dependent RNA polymerase [60],... 

The in vivo protective activity of rifaximin was studied in mice, infected experimentally by intraperitoneal inoculation of S. aureus Colliva and compared to that of rifampicin (a systemic rifamycin) and gentamicin (a poorly absorbed aminoglycoside) [74]. After oral administration, only rifampicin was effective whereas the other two compounds were inactive at doses up to 10 mg/kg. However, when injected subcutaneously, rifaximin displayed a good therapeutic efficacy (table 2). While confirming its antibacterial activity, these results clearly indicate that rifaximin, like gentamycin, is poorly absorbed after oral administration. 

Antimicrobial resistance to rifamycins develops rapidly both in vitro and in vivo [65,85,86], As a consequence, all the three members of the family (i.e. rifampicin, rifabutin and rifapentine) are used clinically as components of combination therapies [65,87], Being structurally related, rifaximin could share this potential. And indeed resistance rates, recorded in fecal strains of Enterobacteriaceae, Enterococcus, Bacteroides, Clostridium and anaerobic cocci, ranged between 30 and 90% after short-term (5 days) antibiotic (800 mg daily) treatment [82], A similar pattern was observed in 10 patients with hepatic encephalopathy after treatment with rifaximin 1,200 mg/day for 5 days [80]. 

The first study was performed by Venturini [97, 98] in both rats and dogs by using a microbiological assay (i.e. agar diffusion test and S. aureus 209 P FDA as test organism). Conversely from rifampicin, whose serum levels were already detectable 30 min after the administration and still measurable after 48 h, only trace amounts (i.e. 0.2 pg/ml) of rifaximin were detected in serum of fed rats 4 h later (fig. 6). The amount of detectable antibiotic was reduced by 50% in fasted animals. Similar results have been obtained in dogs after oral administration of 25 mg/ kg of both rifamycin derivatives [97, 98], No detectable amount of rifaximin was found in serum at any time. 

Mycobacteria are also killed in vitro, as expected from an antibiotic sharing the properties of the rifamycin family [24], In a study by Soro et al. [25], the MIC of rifaximin was determined for five Mycobacterium tuberculosis isolates from patients with tuberculosis. MIC concentrations were studied at 6, 20, 90 and 270 pg/ml, respectively. No resistant organisms were found. Growing M. tuberculosis in the presence of varying doses of rifaximin did not induce the occurrence of rifampicin-resistant strains [25]. In addition to this, experimental tubercular infection in the guinea pig was found not to be affected by an oral treatment course with rifaximin, therefore confirming the lack of absorption of the molecule after oral administration [26],... 

Fig. 4.7 Structures of (A) rifamycin, (B) rifampicin and (C) rifabutin, together with their pharmacokinetic properties. Voiume of distribution V i) and plasma clearance (Cip) are for free unbound drug.

Rifamycin SV (133, Fig. 23) is a naturally occurring macrocycle isolated from Nocardia mediterranei by Senti, Greco and Ballotta in 1959. It shows a high in vitro antibiotic activity through inhibition of DNA-dependent RNA polymerase, but bioavailability is low due to its poor water solubility. The semisynthetic derivative rifampicin (135) displays markedly higher water solubility and in vivo activity. We chose 3-formylrifamycin (134) as model macrocycle for the possibility of binding it to solid phase by hydrazone bond formation in a manner similar to rifampicin (Fig. 24). 

Rifabutin is a rifamycin used for prophylaxis against Mycobacterium avium complex infections in patients with low CD4 count. As with rifampicin it induces hepatic enzymes, although to a lesser extent than rifampicin, and the effectiveness of some drugs including oral contraceptives may be reduced. 

Among the antimycobacterials often a differentiation is made between first-choice and second-choice agents. The first-choice agents include iso-niazid, rifampicin, ethambutol, pyrazinamide and streptomycin or as alternatives the other aminoglycosides amikacine or kanamycine. The second-choice agents include the quinolones ciprofloxacin and ofloxacin and also the rifamycin derivative rifabutin. 

Rifampicin, a semisynthetic derivative of the antimicrobial agent rifamycin B obtained from Strep-tomyces mediterranei, is bactericidal for intra- and extracellular bacteria. Bacterial RNA synthesis is inhibited by binding to the beta-subunit of DNA-dependent RNA polymerase. Human polymerases are not affected. It has activity against gram-positive and gram-negative cocci, chlamydia as well as mycobacteria. It is used in combination with dapsone for leprosy. 

The rifamycins, a class of antibacterials isolated from Streptomyces mediterranei, contain a macrocyclic ring bridging across two nonadjacent positions on an aromatic system. Rifampicin (9.96), a semisynthetic derivative of rifamycin, is a drug of choice in the treatment of tuberculosis as well as leprosy, either alone or in combination with other drugs. Rifampicin is much safer than other antituberculotics since it inhibits DNA-directed RNA polymerase in bacteria but not in mammals. Another rifamycin, rifabutin (9.97), is a spiroimidazopiperidyl derivative of the rifamycin. 

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