Dalfopristin
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| AHFS/Drugs.com | International Drug Names |
| MedlinePlus | a603007 |
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| Eliminationhalf-life | 1 hour |
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| Chemical and physical data | |
| Formula | C34H50N4O9S |
| Molar mass | 690.85g·mol−1 |
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Dalfopristinis a semi-syntheticstreptograminantibioticanalogue of ostreogyrcin A (virginiamycin M,pristinamycin IIA,streptogramin A).[1]The combinationquinupristin/dalfopristin(marketed under the trade nameSynercid) was brought to the market byRhone-Poulenc Rorer Pharmaceuticalsin 1999.[2]Synercid(weight-to-weight ratio of 30%quinupristinto 70% dalfopristin) is used to treatinfectionsbystaphylococciand byvancomycin-resistantEnterococcus faecium.[3]
Synthesis[edit]
Through theadditionof diethylaminoethylthiol to the 2-pyrrolinegroup andoxidationof thesulfateof ostreogrycin A, a structurally morehydrophobiccompound is formed. Thishydrophobiccompound contains a readilyionizablegroup that is available for salt formation.[1]
Large Scale Preparation[edit]
Dalfopristin is synthesized frompristinamycine IIathrough achieving a stereoselectiveMichael-type additionof 2-diethylaminoethanethiol on the conjugated double bond of the dehydroproline ring[4] . The first method found was usingsodium periodateassociated withruthenium dioxideto directly oxidize the sulfur derivative into asulfone.However, usinghydrogen peroxidewithsodium tungstatein 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 ofquinupristin/dalfopristinis achieved through purifying cocrystallization of the quinupristin and dalfopristin fromacetonesolutions.[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 andquinupristinhave modestin vitrobacteriostaticactivity. However, 8-16 times higher in vitrobactericidalactivity is seen against manygram-positive bacteriawhen the twostreptograminsare combined[5] . Whilequinupristin/dalfopristinis effective againststaphylococciandvancomycin-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 theribosome.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 inhibitsprotein synthesisthrough 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 instaphylococcalandenterococcalspecies through production of dalfopristin-inactivating acetyltransferase or quinupristin-inactivating hydrolase. Efflux or active transport of the drug may occur in coagulase-negative staphylococci andEnterococcus 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/dalfopristinoffers 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 ofcytochrome P450(CYP) 3A4 enzyme pathway.[5]Caution should be taken with concommitent use with drugs metabolized by theCYP3A4pathway. Concomitant use ofquinupristin/dalfopristinwithcyclosporinefor 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 withhepatic impairmentand no recommendations by the manufacturer have been made for dose reduction ofquinupristin/dalfopristinin 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 amesylatesalt.[citation needed]
References[edit]
- ^ab"Dalfopristin (as mesylate) (CAS 112362-50-2)".Santa Cruz Biotechnology, Inc.
- ^ab"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.PMID11219478.
- ^abBarrière 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.PMID10197038.
- ^abcdeAllington DR, Rivey MP (January 2001). "Quinupristin/dalfopristin: a therapeutic review".Clinical Therapeutics.23(1): 24–44.doi:10.1016/S0149-2918(01)80028-X.PMID11219478.