Rifapentin Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
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.
Chemische Eigenschaften
Crystalline Solid
Verwenden
Semi-synthetic rifamycin. Antibacterial (tuberculostatic)
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.
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.
Hazard
Moderately toxic by ingestion.
Pharmazeutische Anwendungen
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.
Pharmakokinetik
Oral absorption：c. 70%
C
max600 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.
DistributionAnimal 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.
MetabolismThe 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.
excretionThe 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)
Nebenwirkungen
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).
Rifapentin Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
