Chemical Properties
Crystalline Solid
Usage
antibacterial (tuberculostatic);'inhibits DNA-dependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis
Usage
PDE5 inhibitor for erectile dysfunction A semisynthetic ansamycin antibiotic, cyclopentyl derivative of Rifamycin. Treatment of pulmonary tuberculosis
Usage
Semi-synthetic rifamycin. Antibacterial (tuberculostatic)
Hazard
Moderately toxic by ingestion.
Description
Rifapentine is a broad spectrum antibiotic highly active against Gram-positive bacteria
and Neisseria gonorrhoea. It is reported to be 10 times more active than the structurally
related rifampicin against Mycobacrerim fuberculosis. Unlike rifampicin the
bioavailability of rifapentine is significantly increased when administered after a meal.
Originator
Shanghai No. 5 Factory (China)
Uses
antibacterial (tuberculostatic);'inhibits DNA-dependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis
Uses
PDE5 inhibitor for erectile dysfunction A semisynthetic ansamycin antibiotic, cyclopentyl derivative of Rifamycin. Treatment of pulmonary tuberculosis
Uses
Semi-synthetic rifamycin. Antibacterial (tuberculostatic)
Definition
ChEBI: Rifapentine is a N-alkylpiperazine, a N-iminopiperazine and a member of rifamycins. It has a role as an antitubercular agent and a leprostatic drug.
Indications
Rifapentine is an analogue of rifampin that is active
against M. tuberculosis and M. avium. Rifapentine’s
mechanism of action, cross-resistance, hepatic induction
of P450 enzymes, drug interactions, and toxic profile
are similar to those of rifampin. It has been used in
the treatment of tuberculosis caused by rifampinsusceptible
strains.
Brand name
Priftin (Sanofi Aventis);Rifampin.
Antimicrobial activity
Activity is similar to that of rifampicin, but it is more active against atypical mycobacteria, especially the M. avium complex (MIC <0.06–0.5 mg/L). It has good activity on staphylococci and streptococci (MIC 0.01–0.5 mg/L), L. monocytogenes and Brucella spp.; less against Enterococcus faecalis (MIC 1–4 mg/L). Bacteroides spp. are inhibited by 0.5–2 mg/L. Gram-negative cocci are susceptible and, although some Gram-negative bacilli are inhibited by 4–32 mg/L, most are resistant.
Pharmaceutical Applications
An analog of rifampicin in which a cyclopentyl group is substituted for a methyl group on the piperazine ring. It is available for oral administration.
Mechanism of action
Because relapse and the emergence of resistant strains of bacteria are associated with poor patient compliance, reduced dosing is expected to increase compliance. Initial clinical studies actually showed that the relapse rates in patients treated with rifapentine (10%) were higher than those in the patients treated with RIF (5%). It was found that poor compliance with the nonrifamycin antituberculin agents was responsible for the increased relapse.
Pharmacokinetics
Oral absorption：c. 70%
Cmax600 mg oral ：12 mg/L after 5 h
Plasma half-life：13 h
Volume of distribution：1.5 L/kg
Plasma protein binding：97%
absorption
The absolute oral bioavailability of rifapentine has not been determined. The relative bioavailability of capsules (with an oral solution as reference) is 70%. Food increases absorption: a 600 mg dose taken after a meal gives Cmax and AUC values 44% higher than under fasting conditions. The extended halflife provides therapeutic concentrations for at least 72 h after administration, allowing less frequent dosing.
Distribution
Animal data suggest that it is well distributed in the body, with tissue concentrations exceeding the plasma concentration, except in bone, testes and brain. The ratio of intracellular:extracellular concentration in macrophages was estimated as 24:1.
Metabolism
The main metabolite is an antimicrobially active 25-desacetyl derivative. Although it induces liver cytochromes it is not an inducer of its own metabolism, which is mediated by an esterase. The peak concentration of 25-desacetyl rifapentine is about one-third of that of the unchanged drug, and is attained after about 11 h.
excretion
The main route of elimination is through the bile. In healthy volunteers about 70% of a 600 mg dose of 14C rifapentine was recovered in the feces, and less than 17% in the urine. There is evidence of enterohepatic recycling in humans.
Clinical Use
Tuberculosis (in combination with other antituberculosis drugs)
Side effects
Signs of teratogenic effects and fetal toxicity have been observed when administered during pregnancy to rats and rabbits. Rifapentine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The most common adverse effect observed in combinations with other antimycobacterial agents was hyperuricemia, most probably due to pyrazinamide. Effects likely to be due to rifapentine were neutropenia (3.7% of patients) and hepatitis (increased transaminases in 1.6% of patients).
Synthesis
A method for the preparation of rifapentine, comprising the steps of:
A. using rifamycin S as a starting material, reacting with dihydroxymethyltert-butylamine in a first organic solvent to convert to the intermediate rifaxazin;
in vitro
the activities of rifampin and rifapentine against mycobacterium tuberculosis residing in human monocytederived macrophages were determined. the mic and mbc of rifapentine for intracellular bacteria were two- to four-fold lower than those of rifampin. for extracellular bacteria, this difference was less noticeable. [1].
in vivo
once-a-week exposure to rifapentine concentrations equivalent to that attained in blood after one 600-mg dose resulted during the first week in a dramatic decline in the number of bacteria, and such decline was maintained at a minimal level for a period of four weeks. the prolonged effect of rifapentine found may be associated with high ratios of intracellular accumulation, which were four- to fivefold higher than those found for rifampin [1].
References
[1] mor n, simon b, mezo n, heifets l. comparison of activities of rifapentine and rifampin against mycobacterium tuberculosis residing in human macrophages. antimicrob agents chemother. 1995 sep;39(9):2073-7.
[2] temple me, nahata mc. rifapentine: its role in the treatment of tuberculosis. ann pharmacother. 1999 nov;33(11):1203-10.
