Dalfopristin
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| AHFS/Drugs.com | International Drug Names |
| MedlinePlus | a603007 |
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| Elimination half-life | 1 hour |
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| Formula | C34H50N4O9S |
| Molar mass | 690.85 g·mol−1 |
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Dalfopristin is a semi-synthetic streptogramin antibiotic analogue of ostreogyrcin A (virginiamycin M, pristinamycin IIA, streptogramin A).[1] The combination quinupristin/dalfopristin (marketed under the trade name Synercid) was brought to the market by Rhone-Poulenc Rorer Pharmaceuticals in 1999.[2] Synercid (weight-to-weight ratio of 30% quinupristin to 70% dalfopristin) is used to treat infections by staphylococci and by vancomycin-resistant Enterococcus faecium.[3]
Synthesis[edit]
Through the addition of diethylaminoethylthiol to the 2-pyrroline group and oxidation of the sulfate of ostreogrycin A, a structurally more hydrophobic compound is formed. This hydrophobic compound contains a readily ionizable group that is available for salt formation.[1]
Large Scale Preparation[edit]
Dalfopristin is synthesized from pristinamycine IIa through achieving a stereoselective Michael-type addition of 2-diethylaminoethanethiol on the conjugated double bond of the dehydroproline ring [4] . The first method found was using sodium periodate associated with ruthenium dioxide to directly oxidize the sulfur derivative into a sulfone. However, using hydrogen peroxide with sodium tungstate in a 2-phase medium produces an improved yield, and is therefore the method of choice for large scale production.[citation needed]
The production of the dalfopristin portion of quinupristin/dalfopristin is achieved through purifying cocrystallization of the quinupristin and dalfopristin from acetone solutions.[4]
Physical Characteristics (as mesylate salt)[edit]
| Appearance | White to yellow solid |
| Physical state | Solid |
| Solubility | Soluble in ethanol, methanol, DMSO, DMF, and water (0.072 mg/ml) |
| Storage | -20 °C |
| Boiling point | 940.5 °C at 760 mmHg |
| Melting point | 150 °C |
| Density | 1.27 g/cm3 |
| Refractive index | n20D 1.58 |
| pK values | pKa: 13.18 (Predicted), pKb: 8.97 (Predicted) |
Antimicrobial activity[edit]
Alone, both dalfopristin and quinupristin have modest in vitro bacteriostatic activity. However, 8-16 times higher in vitro bactericidal activity is seen against many gram-positive bacteria when the two streptogramins are combined [5] . While quinupristin/dalfopristin is effective against staphylococci and vancomycin-resistant Enterococcus faecium, in vitro studies have not demonstrated bactericidal activity against all strains and species of common gram-positive bacteria.[citation needed]
Mechanism of action[edit]
Both dalfopristin and quinupristin bind to sites located on the 50S subunit of the ribosome. Initial dalfopristin binding results in a conformational change of the ribosome, allowing for increased binding by quinupristin.[5] A stable drug-ribosome complex is created when the two drugs are used together. This complex inhibits protein synthesis through prevention of peptide-chain formation and blocking the extrusion of newly formed peptide chains. In many cases, this leads to bacterial cell death.[citation needed]
Mechanism of resistance[edit]
Streptogramin resistance is mediated through enzymatic drug inactivation, efflux or active transport of drug out of the cell, and most commonly, conformational alterations in ribosomal target binding sites.[5] Enzymatic drug inactivation may occur in staphylococcal and enterococcal species through production of dalfopristin-inactivating acetyltransferase or quinupristin-inactivating hydrolase. Efflux or active transport of the drug may occur in coagulase-negative staphylococci and Enterococcus faecium. Constitutive ribosome modification has been seen in staphylococci with resistance seen in quinupristin only.[citation needed]
While resistance to dalfopristin may be conferred via a single point of mutation, quinupristin/dalfopristin offers the benefit of requiring multiple points of mutation targeting both dalfopristin and quinupristin components to confer drug resistance.[5] Comparatively, only 2-5% of staphylococcal isolates collected in France show resistance to a related streptogramin, pristinamycin, in over 35 years of use.[citation needed]
Drug interactions[edit]
Both dalfopristin and quinupristin are extensively hepatically metabolized, excreted from the feces, and serve as an inhibitor of cytochrome P450 (CYP) 3A4 enzyme pathway.[5] Caution should be taken with concommitent use with drugs metabolized by the CYP3A4 pathway. Concomitant use of quinupristin/dalfopristin with cyclosporine for 2–5 days has shown to result in a two-fold increase in cyclosporine levels.[citation needed]
No adverse effects have been seen in patients with hepatic impairment and no recommendations by the manufacturer have been made for dose reduction of quinupristin/dalfopristin in this patient population.[citation needed]
Commercialization[edit]
While little information is available regarding the regulatory and commercialization history of Dalfopristin alone, Synercid (quinupristin/dalfopristin), made by Rhone-Poulenc Rorer Pharmaceuticals, was approved in 1999 as an IV injectable for the treatment of vancomycin resistant Enterococcus faecium and complicated skin and skin structure infections.[2] Dalfopristin can be purchased alone on the internet from various chemical manufacturers as a mesylate salt.[citation needed]
References[edit]
- ^ a b "Dalfopristin (as mesylate) (CAS 112362-50-2)". Santa Cruz Biotechnology, Inc.
- ^ a b "Synercid (Quinupristin/Dalfopristin) I.V." Drug Approval Package. U.S. Food and Drug Administration.
- ^ Allington DR, Rivey MP (January 2001). "Quinupristin/dalfopristin: a therapeutic review". Clinical Therapeutics. 23 (1): 24–44. doi:10.1016/S0149-2918(01)80028-X. PMID 11219478.
- ^ a b Barrière JC, Berthaud N, Beyer D, Dutka-Malen S, Paris JM, Desnottes JF (April 1998). "Recent developments in streptogramin research". Current Pharmaceutical Design. 4 (2): 155–80. PMID 10197038.
- ^ a b c d e Allington DR, Rivey MP (January 2001). "Quinupristin/dalfopristin: a therapeutic review". Clinical Therapeutics. 23 (1): 24–44. doi:10.1016/S0149-2918(01)80028-X. PMID 11219478.