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Rifapentine (formerly also known as MDL473; Priftin; DL 473, Cyclopentylrifampicin) is a potent antibiotic/antimicrobial of the rifamycin class, used to treat tuberculosis. It inhibits DNA-dependent RNA polymerase activity. Rifapentine inhibits the function of DNA-dependent RNA polymerase in strains of M. tuberculosis, while inducing no effect on mammalian cells. Both Rifapentine and its active metabolite, 25-desacetylrifapentine, localize within monocyte-derived macrophages, thus allowing for intracellular inhibition of M. tuberculosis at a greater kill rate as compared with that of the parent or metabolite alone. Rifapentine is deacetylated in the liver and induces cytochrome P450 much less than rifampin.
Physicochemical Properties
| Molecular Formula | C47H64N4O12 | |
| Molecular Weight | 877.03 | |
| Exact Mass | 876.452 | |
| Elemental Analysis | C, 64.37; H, 7.36; N, 6.39; O, 21.89 | |
| CAS # | 61379-65-5 | |
| Related CAS # | Rifapentine-d9 | |
| PubChem CID | 135403821 | |
| Appearance | Solid powder | |
| Density | 1.4±0.1 g/cm3 | |
| Boiling Point | 969.3±65.0 °C at 760 mmHg | |
| Melting Point | 179-180ºC | |
| Flash Point | 540.0±34.3 °C | |
| Vapour Pressure | 0.0±0.3 mmHg at 25°C | |
| Index of Refraction | 1.625 | |
| LogP | 2.58 | |
| Hydrogen Bond Donor Count | 6 | |
| Hydrogen Bond Acceptor Count | 15 | |
| Rotatable Bond Count | 6 | |
| Heavy Atom Count | 63 | |
| Complexity | 1730 | |
| Defined Atom Stereocenter Count | 9 | |
| SMILES | OC(C1=C(C2=O)C(O[C@@]2(O/C=C/[C@@H]([C@H]([C@@]([C@@H]3C)([H])OC(C)=O)C)OC)C)=C(C)C(O)=C1C(O)=C4NC(/C(C)=C\C=C\[C@@H]([C@@H]([C@@H](C)[C@H]3O)O)C)=O)=C4/C=N/N5CCN(C6CCCC6)CC5 |
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| InChi Key | WDZCUPBHRAEYDL-GZAUEHORSA-N | |
| InChi Code | InChI=1S/C47H64N4O12/c1-24-13-12-14-25(2)46(59)49-37-32(23-48-51-20-18-50(19-21-51)31-15-10-11-16-31)41(56)34-35(42(37)57)40(55)29(6)44-36(34)45(58)47(8,63-44)61-22-17-33(60-9)26(3)43(62-30(7)52)28(5)39(54)27(4)38(24)53/h12-14,17,22-24,26-28,31,33,38-39,43,53-57H,10-11,15-16,18-21H2,1-9H3,(H,49,59)/b13-12+,22-17+,25-14-,48-23+/t24-,26+,27+,28+,33-,38-,39+,43+,47-/m0/s1 | |
| Chemical Name | 3-(N-(4-Cyclopentyl-1-piperazinyl)formimidoyl)rifamycin | |
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| HS Tariff Code | 2934.99.03.00 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
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| ln Vivo |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Rapidly and well absorbed from the gastrointestinal tract. Following a single 600 mg oral dose of radiolabeled rifapentine to healthy volunteers (n=4), 87% of the total 14C rifapentine was recovered in the urine (17%) and feces (70%). 70.2 ± 9.1 L Apparent Oral cl=2.51 +/- 0.14 L/h [Male tuberculosis patients who received 600 mg rifapentine in combination with isoniazid, pyrazinamide and ethambutol] Apparent Oral cl=1.69 +/- 0.41 L/h [Female tuberculosis patients who received 600 mg rifapentine in combination with isoniazid, pyrazinamide and ethambutol] Metabolism / Metabolites Hepatic |
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| Toxicity/Toxicokinetics |
Hepatotoxicity Because of its limited use, the effects of rifapentine on the liver have been less well defined than those of rifampin, but they are likely to be similar. Thus, long term therapy with rifapentine is associated with minor, transient elevations in serum aminotransferase levels in 2% to 7% of patients, abnormalities that usually do not require dose adjustment or discontinuation. Clinically apparent liver injury due to rifapentine has not been reported, but it is likely to be similar to rifampin in its potential for causing acute liver injury. Because rifapentine is usually given in combination with isoniazid and/or pyrazinamide, two other known hepatotoxic agents, the cause of the acute liver injury in patients on rifapentine containing regimens may be difficult to relate to a single agent, and some evidence suggests that these combinations are more likely to cause injury than the individual drugs. Typically, the onset of injury due to rifamycins is within 1 to 6 weeks and the serum enzyme pattern is usually hepatocellular at the onset of injury, but can cholestatic and mixed in contrast to isoniazid and pyrazinamide. Extrahepatic manifestations due to rifamycin hepatotoxicity such as fever, rash, arthralgias, edema and eosinophilia are uncommon as is autoantibody formation. This potential for hepatotoxicity has not been specifically demonstrated for rifapentine. Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation The amount of rifapentine and its metabolite in milk is insufficient to treat tuberculosis in the breastfed infant. The Centers for Disease Control and Prevention and other professional organizations state that breastfeeding should not be discouraged in women taking rifapentine. Monitor the infant for signs of liver toxicity. Breastmilk may be stained a red-orange color. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding 97.7% (bound to plasma proteins) |
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| References | Ann Pharmacother.1999 Nov;33(11):1203-10;Antimicrob Agents Chemother.1995Sep;39(9):2073-7;Drugs.1998 Oct;56(4):607-16; discussion 617. | ||
| Additional Infomation |
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. Rifapentine is an antibacterial prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of active tuberculosis (TB) of the lungs. (Active TB is also called TB disease.) Rifapentine is also FDA-approved for the treatment of latent TB infection to prevent the infection from advancing to active TB disease. TB can be an opportunistic infection (OI) of HIV. Rifapentine is an antibiotic drug used in the treatment of tuberculosis. It inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. Rifapentine is a Rifamycin Antimycobacterial. Rifapentine is a rifamycin antibiotic that is similar in structure and activity to rifampin and rifabutin and that is used in combination with other agents as therapy of tuberculosis, particularly in once or twice weekly regimens. Rifapentine is associated with transient and asymptomatic elevations in serum aminotransferase and is a likely cause of clinically apparent acute liver injury. Rifapentine is a long-acting, cyclopentyl-substituted derivative of rifamycin used to treat mycobacterium infections. See also: Rifapentine hydrochloride (is active moiety of). Drug Indication For the treatment of pulmonary tuberculosis. Mechanism of Action Rifapentine has shown higher bacteriostatic and bactericidal activities especially against intracellular bacteria growing in human monocyte-derived macrophages. Rifapentine inhibits DNA-dependent RNA polymerase in susceptible strains of M. tuberculosis. Rifapentine acts via the inhibition of DNA-dependent RNA polymerase, leading to a suppression of RNA synthesis and cell death. Pharmacodynamics Rifapentine is an antibiotic that inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. It is bactericidal and has a very broad spectrum of activity against most gram-positive and gram-negative organisms (including Pseudomonas aeruginosa) and specifically Mycobacterium tuberculosis. Because of rapid emergence of resistant bacteria, use is restricted to treatment of mycobacterial infections and a few other indications. Rifampin is well absorbed when taken orally and is distributed widely in body tissues and fluids, including the CSF. It is metabolized in the liver and eliminated in bile and, to a much lesser extent, in urine, but dose adjustments are unnecessary with renal insufficiency. |
Solubility Data
| Solubility (In Vitro) |
DMSO : 50 ~100 mg/mL ( 57.01 ~114.02 mM ) H2O : ~0.67 mg/mL (~0.76 mM) Ethanol : ~10 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.85 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (2.85 mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1402 mL | 5.7011 mL | 11.4021 mL | |
| 5 mM | 0.2280 mL | 1.1402 mL | 2.2804 mL | |
| 10 mM | 0.1140 mL | 0.5701 mL | 1.1402 mL |