Desacetyl-rifamycins: Preparation and antibacterial properties

The new oral 200-mg rifamycin SV MMX modified-release tablets, designed to deliver rifamycin SV directly into the colonic lumen, offer considerable advantages over the existing immediate-release antidiarrheic formulations. In two pharmacokinetics studies of healthy volunteers, the absorption, urinary excretion, and fecal elimination of rifamycin SV after single-and multiple-dose regimens of the new formulation were investigated. Concentrations in plasma of >2 ng/ml were infrequently and randomly quantifiable after single and multiple oral doses. The systemic exposure to rifamycin SV after single and multiple oral doses of MMX tablets under fasting and fed conditions or following a four-times-a-day (q.i.d.) or a twice-a-day (b.i.d.) regimen could be considered negligible. With both oral regimens, the drug was confirmed to be very poorly absorbable systemically. The amount of systemically absorbed antibiotic excreted by the renal route is far lower than 0.01% of the administered dose after both the single-and multiple-dose regimens. The absolute bioavailability, calculated as the mean percent ratio between total urinary excretion amounts (⌺Xu) after a single intravenous injection and after a single oral dose under fasting conditions, was 0.0410 ؎ 0.0617. The total elimination of the unchanged rifamycin SV with feces was 87% of the administered oral dose. No significant effect of rifamycin SV on vital signs, electrocardiograms, or laboratory parameters was observed.

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“…Rifamycin SV can hydrolyze in vivo and after de-esterification forms the 25-desacetyl metabolite (1,15).…”

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confidence: 99%

Systemic Absorption of Rifamycin SV MMX Administered as Modified-Release Tablets in Healthy Volunteers

Stefano¹,

Rusca²,

Loprete³

et al. 2011

Antimicrob Agents Chemother

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“…Rifabutin (pharmaceutical formula) and 6‐aminonicotinic acid (98% purity, Sigma Chemical Co.) were used as internal standards (ISs). 25‐Desacetylrifampicin was prepared by alkaline hydrolysis of the parent rifampicin, as previously described,19 and acetylisoniazid was synthesized by the method of Fox and Gibas 20…”

Section: Methodsmentioning

confidence: 99%

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Soldatov¹,

Ripmeester²

2001

Chem. Eur. J.

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“…F3AcNHEtS-Ric 3-(2-Aminoethyl)-thiorifamycin SV [28] in dimethylformamide was reacted with an excess of S-ethyl trifluorothioacetic acid. The desired product was isolated as an amorphous material by silica gel column chromatography with the solvent mixture chloroform/ethanol (2/1, v/v).…”

Section: Synthesis Of Rifamycin Sv Derivativesmentioning

confidence: 99%

Studies of the Topography of the Binding Site of DNA-Dependent RNA Polymerase from Escherichia coli for the Antibiotic Rifamycin SV

Stender

Scheit

1977

Eur J Biochem

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The synthesis of dimeric derivatives of rifamycin SV differing in the length of spacer, of derivatives of rifamycin SV possessing 2,4-dinitrophenyl groups in varying distances relative to the aromatic part of the antibiotic and a derivative of rifamycin SV carrying a biotinyl residue is described. Rifamycin SV covalently attached to bovine serum albumin was employed to produce antibodies against rifamycin SV in rabbits. Rifamycin SV as well as 2,4-dinitrophenyl-specific antibodies and avidin were used to study the interaction of RNA polymerase with the respective derivatives of rifamycin SV. The results of this investigation can be summarized as follows.1. Antibodies, which are specific for rifamycin SV do not recognize the rifamycin SV molecule in the enzyme . antibiotic complex.2. 2,4-Dinitrophenyl-specific antibodies are unable to recognize the 2,4-dinitrophenyl residue in the complex enzyme . 2,4-dinitrophenylaminoethylthio-rifamycin-SV.3. However, 2,4-dinitrophenyl groups in complexes between enzyme and 2,4-dinitrophenyl derivatives of rifamycin SV are recognized, if those are separated far enough from the rifamycin part.4. RNA polymerase binds to the rifamycin SV portion in complexes avidin . biotinylaminoethylthio-rifamycin-SV.5. Dimeric rifamycin SV molecules do not form ternary complexes with RNA polymerase. From those results it is concluded that the binding site of RNA polymerase for rifamycin SV extends 1.40 -1.90 nm deep into the interior of the enzyme structure and that the ansa chain of the antibiotic extends furthest into the enzyme Rifamycin SV and its derivaties are strong inhibitors of DNA-dependent RNA synthesis in bacteria [I -51. They interfere with chain initiation of RNA synthesis when binding to the enzyme, RNA polymerase, or to the complex RNA-polymerase . DNA [6,7]. Recent investigations yield evidence that the first phosphodiester bond is still formed in the presence of the antibiotic and that the steps of the enzymatic reaction, which lead to the elongation of the phosphodiester bond, are inhibited [8]. Kinetic and thermodynamic studies reveal the high affinity of rifampicin and other rifamycin SV derivatives to enzyme or enzyme . DNA complexes [9-121. Little is known about the topology of the antibiotic binding site of Abbreviations. The abbreviations of the various synthetic derivatives of rifamycin SV are given in Table 2; Nzph = dinitrophenyl.Enzyme. DNA-dependent RNA polymerase (EC 2.7.7.6).RNA polymerase. An investigation of a rifampicininsensitive RNA polymerase from Escherichia coli and affinity labelling studies with chemically reactivederivatives of rifamycin SV demonstrate that the p subunit seems to carry the antibiotic binding site [13,14]. The affinity labelling experiments indicate that the bound rifamycin SV is in contact with o subunit. Structure-activity relations based on chemical modifications of the antibiotic affecting the activity indicate that both the ansa ring, as well as the aromatic part of the antibiotic, are involved in the interaction with the enzyme (F...

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Desacetyl-rifamycins: Preparation and antibacterial properties

Cited by 23 publications

References 4 publications

Systemic Absorption of Rifamycin SV MMX Administered as Modified-Release Tablets in Healthy Volunteers

Systemic Absorption of Rifamycin SV MMX Administered as Modified-Release Tablets in Healthy Volunteers

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Studies of the Topography of the Binding Site of DNA-Dependent RNA Polymerase from Escherichia coli for the Antibiotic Rifamycin SV

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