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Penicillamin
PENICILLAMINE · Penicillamin · 2-Amino-3-mercapto-3-methylbutanoic acid · (S)-2-aMino-3-Mercapto-3-Methylbutanoic acid · Pencillamine · usan · H-D-PEN-OH · Depen
Identifikatoren & physikalische Daten
| CAS No. | 52-67-5 |
|---|---|
| Summenformel | C5H11NO2S |
| Durchschnittliche Molmasse | 149,21 g/mol |
| Monoisotopische Masse | 149,05104977 g/mol |
| SMILES | CC(C)(S)[C@@H](N)C(=O)O |
| InChIKey | VVNCNSJFMMFHPL-VKHMYHEASA-N |
| PubChem CID | 5852 |
| ChEMBL | CHEMBL1430 |
| ChEBI | CHEBI:7959 |
| EC No. | 200-148-8 |
| DTXSID | DTXSID6037069 |
| Lokaler Name | Penicillamin |
Chemische & physikalische Eigenschaften
| XLogP | -1,8 |
|---|---|
| Polarare Oberfläche (TPSA) | 64,3 |
| H-Brücken-Donoren | 3 |
| H-Brücken-Akzeptoren | 4 |
| Frei drehbare Bindungen | 2 |
| Schwere Atome | 9 |
| Formalladung | 0 |
| Komplexität | 124 |
| LogP (Verteilungskoeffizient) | -1.78 |
| LogS | -0.13 |
| Geruch | SLIGHT CHARACTERISTIC ODOR |
| Geschmack | SLIGHTLY BITTER |
| Color/Form | FINE, WHITE OR PRACTICALLY WHITE, CRYSTALLINE POWDER |
| Löslichkeit | 111000CRYSTALSDECOMP 177.5 °CSPECIFIC OPTICAL ROTATION: -63 DEG @ 25 °C/D (1N SODIUM HYDROXIDE)HYGROSCOPICFREELY SOL IN WATER, SOL IN ETHANOL. /D-PENICILLAMINE HYDROCHLORIDE/FREELY SOL IN WATERSLIGHTLY SOL IN ALCINSOL IN ETHER, CHLOROFORM.H2O: soluble100mg/mL11.1 g/100 mL (20 ºC) |
| Decomposition | When heated to decomposition it emits very toxic fumes of oxides of nitrogen and oxides of sulfur. |
| Schmelzpunkt | 198.5202-206 °C210 °C (dec.)(lit.) |
| Optical Rotation | SPECIFIC OPTICAL ROTATION: -63 DEG @ 25 °C/D (CONCENTRATION BY VOLUME = 0.1 G IN 100 ML PYRIDINE) |
| Stability/Shelf Life | RELATIVELY STABLE IN BOTH LIGHT & AIR.AQ SOLN IS COMPARATIVELY STABLE @ PH 2-4 |
| Dissociation Constants | 7.831.8 |
| Other Experimental Properties | CRYSTALSDECOMP 201 °CPK VALUES: CARBOXYL 1.8, ALPHA-AMINO 7.9, BETA-THIOL 10.5 /DL-PENICILLAMINE/DECOMP 145-148 °C /DL-PENICILLAMINE HYDROCHLORIDE/MP 190-194 °CSPECIFIC OPTICAL ROTATION: +63 DEG @ 25 °C/D (IN N SODIUM HYDROXIDE). /L-PENICILLAMINE/Decomposes at 178 °C |
| Siedepunkt | 251.8±35.0 °C(Predicted) |
| Dichte | 1.113 (estimate) |
| Brechungsindex | -63 ° (C=1, 1mol/L NaOH) |
| Lagerbedingungen | 2-8°C |
| pKa (Säurekonstante) | pKa 7.83±0.01(H2O,t =37±0.05,I=0.15)(Approximate) |
| Aggregatzustand | Powder |
| Farbe | White to almost white |
| Merck | 14,7088 |
| BRN | 1722375 |
| BCS Class | 3 |
| Stabilität | Stable. Incompatible with strong oxidizing agents. |
| InChI | 1S/C5H11NO2S/c1-5(2,9)3(6)4(7)8/h3,9H,6H2,1-2H3,(H,7,8)/t3-/m0/s1 |
| InChIKey | VVNCNSJFMMFHPL-VKHMYHEASA-N |
| SMILES | CC(C)(S)[C@@H](N)C(O)=O |
| CAS Datenbank | 52-67-5(CAS DataBase Reference) |
| NIST chemische Informationen | Penicillamine(52-67-5) |
| EPA chemische Informationen | Penicillamine (52-67-5) |
Sicherheit & Vorschriften
| GHS-Einstufung | WarningH315 (90.4%): Causes skin irritation [Warning Skin corrosion/irritation]H319 (88.5%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]H335 (84.6%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposureRespiratory tract irritation]P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 52 reports by companies from 11 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website. |
|---|---|
| Regulatorische Informationen | Hazard Traits - Developmental ToxicityAuthoritative List - Prop 65Report - regardless of intended function of ingredient in the product |
| Gefahrenübersicht | Asthma reported in a pharmaceutical worker[Malo] Penicillamine is a drug used to treat several diseases. Many side effects have been reported after ingestion of therapeutic doses, including bone marrow suppression and drug-induced hepatitis. [HSDB] |
| FDA-Anforderungen | Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended21 U.S.C. 321-392).The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl penicillamine, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. |
| Special Reports | HUSKISSON ECEUR J RHEUMATOL INFLAMMATION 3 (2): 156 (1979)REVIEW ARTICLE ON THE RENAL TOXICITY OF PENICILLAMINE.JELLUM E, MUNTHE ENAT SULFUR CMPD, (PROC INT MEET) 3RD: 375 (1980)CLINICAL EFFECTS OF PENICILLAMINE IN THE TREATMENT OF RHEUMATOID ARTHRITIS ARE DISCUSSED.Howard-Lock HE et alD-penicillamine: Chemistry and Clinical Use in Rheumatic Disease. Semin Arthritis Rheum 15 (4): 261-81 (1986). The discovery of D-penicillamine and its uses in medicine are reviewed.Joyce DAD-Penicillamine Pharmacokinetics and Pharmacodynamics in Man. Pharmacol Ther 42 (3): 405-27 (1989). A review of the pharmacokinetics and pharmacodynamics of D-penicillamine is presented, including the mechanism of action of D-penicillamine in the treatment of rheumatoid arthritis and progressive systemic sclerosis.For more Special Reports (Complete) data for (D)-PENICILLAMINE (7 total), please visit the HSDB record page. |
| Hazard Classes and Categories | Skin Irrit. 2 (90.4%)Eye Irrit. 2A (88.5%)STOT SE 3 (84.6%) |
| Lagerbedingungen | Packaging and storage: Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. /Penicillamine capsules USP/Packaging and storage: Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. /Penicillamine tablets USP/ |
| Wechselwirkungen | DOWNWARD ADJUSTMENT OF DOSAGE OF OTHER ANTI-INFLAMMATORY DRUGS, ESP CORTICOSTEROIDS, IS OFTEN POSSIBLE AFTER ADDN OF PENICILLAMINE TO DRUG REGIMEN.Pyridoxine, 10-25 mg/day, should be administered concomitantly because penicillamine inhibits pyridoxal-dependent enzymes.Concurrent use /of 4-aminoquinolines or bone marrow depressants ... or gold compounds or immunosuppressants, excepting glucocorticoids/ with penicillamine may increase the potential for serious hematologic and/or renal adverse reactions.Concurrent use with 4-aminoquinolines may ... increase the risk of severe dermatologic reactions.For more Interactions (Complete) data for (D)-PENICILLAMINE (8 total), please visit the HSDB record page. |
| Hepatotoxicity | Penicillamine has been linked to a characteristic pattern of liver injury arising 1 to 6 weeks after starting therapy, with a distinctly cholestatic pattern of serum enzyme elevations (Case 1). The jaundice due to penicillamine can be severe and prolonged and result in protracted, symptomatic cholestasis, but most cases are self-limited. Immunoallergic manifestations of rash, fever and eosinophilia are common, but not invariable. Interesting, most cases of acute liver injury attributed to penicillamine were reported in patients with rheumatic diseases, only rare instances being reported in Wilson disease.Other toxicities of penicillamine therapy such as bone marrow suppression, neutropenia and severe dermatologic features can accompany the hepatic injury. Furthermore, in instances with severe nonhepatic penicillamine toxicities, some degree of hepatic involvement such as mild-to-moderate serum enzyme elevations may occur. Long term toxicities of penicillamine include induction of autoimmune conditions (glomerulonephritis, pneumonitis, lupus-like syndrome) that may be accompanied by autoantibody formation, but autoimmune hepatitis-like syndromes have not been reported.Likelihood score: A (well established cause of clinically apparent liver injury). |
| Unerwünschte Wirkungen | Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.Asthma - Reversible bronchoconstriction (narrowing of bronchioles) initiated by the inhalation of irritating or allergenic agents.Most Common Adverse Effects* Diarrhea* Dysgeusia* HalitosisLess Common Adverse Effects* Skin rash* Proteinuria* Thrombocytopenia* LeukopeniaRare Adverse Effects* Local thrombophlebitis, vasculitis* Anxiety, agitation, dystonia, Guillain-Barre syndrome, neuropathy, psychiatric disturbance, myasthenia gravis (including extraocular muscles)* Agranulocytosis, aplastic anemia, pure red cell aplasia, sideroblastic anemia, positive ANA titer, thrombotic thrombocytopenic purpura* Increased serum alkaline phosphatase, hepatic failure, intrahepatic cholestasis* Lupus-like syndrome* Diplopia, optic neuritis, visual disturbance* Tinnitus, renal failure, asthma, interstitial pneumonitis, pulmonary fibrosis* Breast disease (mammary hyperplasia), Goodpasture syndrome, hematuria, nephrotic syndrome* Dermatomyositis, polymyositis* Polyarthralgia (migratory, often with objective synovitis) |
| Toxizitätsübersicht | Signs and Symptoms of OverdosePenicillamine overdose can cause symptoms such as nausea, vomiting, diarrhea, and oral ulceration. More serious cases may lead to hematuria, nephrotic syndrome, leukopenia, thrombocytopenia, and confusion or drowsiness. Allergic cutaneous adverse drug reactions and myasthenia gravis can occur.Management of OverdoseThere is no specific antidote for penicillamine overdose. Stopping the D-penicillamine and providing supportive treatment are the primary steps in management. Pyridoxine can be considered. Clinicians need to be familiar with the toxicity of penicillamine, understand special dosing considerations, and never use the drug casually. Patients should be under close clinical supervision and report any symptoms suggestive of toxicity, such as fever, bleeding, bruising, and chills. Gold sodium thiomalate can cause the toxicity of penicillamine and should be avoided. For severe cutaneous adverse drug reactions, stopping penicillamine, administering intravenous immunoglobulin, using systemic corticosteroids, and providing supportive care can be helpful. Contact the national poison control center at 1-800-222-1222 for the latest, evidence-based medicine practices. |
| Human Toxicity Excerpts | ACUTE SENSITIVITY REACTIONS, MANIFESTED BY FEVER, RASHES (PRURITIC, MORBILLIFORM, & URTICARIAL), LEUKOPENIA, EOSINOPHILIA, & THROMBOCYTOPENIA, HAVE BEEN ENCOUNTERED EARLY IN COURSE OF THERAPY. ... INFREQUENTLY, ANOREXIA, NAUSEA, & VOMITING OCCUR. LOSS OF TASTE FOR SALT & SWEET HAS BEEN OBSERVED.Serious reactions involving the hematologic system (thromobocytopenia, leukopenia, agranulocytosis, aplastic anemia) and renal system (proteinuria, hypoalbuminemia, nephrotic syndrome. ... Other serious reactions reported occasionally are lupus-like disease, pemphigus, goodpasture's syndrome, mysthenia gravis, and dermatomyositis or polymyositis.SEVERAL CASES OF NEPHROTOXICITY, INCL PATIENTS GIVEN ONLY D-PENICILLAMINE, HAVE BEEN REPORTED. PRESUMABLY ... RESULT FROM HYPERSENSITIVITY REACTIONS. CASE OF OPTIC NEURITIS ... HAS ALSO OCCURRED. ... AFTER THERAPY FOR 1-2 YEAR'S DURATION,SYSTEMIC LUPUS ERYTHEMATOSUS-LIKE SYNDROME ... OBSERVED.TOXIC EFFECTS ON EYE HAVE BEEN RARE, CONSISTING OF ISOLATED CASES OF OPTIC NEURITIS, RETINAL HEMORRHAGE, MYOPIA, & SUPERFICIAL INFLAMMATION & IRRITATION OF EYES ASSOC WITH DERMATITIS.For more Human Toxicity Excerpts (Complete) data for (D)-PENICILLAMINE (21 total), please visit the HSDB record page. |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)PenicillaminevLess-DILI-concernWarnings & precautionsDOI:10.1016/j.drudis.2016.02.015 |
| Non-Human Toxicity Excerpts | ADMIN OF 500 MG/KG/DAY ORALLY TO MALE RATS FOR 60 DAYS BEFORE MATING DECR BODY WT GAIN, FOOD CONSUMPTION, SPONTANEOUS LOCOMOTOR ACTIVITY, & FERTILITY. HOWEVER, PENICILLAMINE ADMIN TO FEMALES FOR 14 DAYS BEFORE & 7 DAYS AFTER MATING DID NOT.SINGLE ORAL DOSE ADMIN TO HAMSTERS ON DAY 7 OF GESTATION CAUSED INCR FETAL MORTALITY, GROWTH RETARDATION & MALFORMATION. MOST SEVERE MALFORMATIONS WERE EXENCEPHALY & ENCEPHALOCELE.1000 MG/KG/DAY GIVEN ORALLY TO RATS FROM DAY 7 TO DAY 17 OF GESTATION PRODUCED DISARRANGEMENT OF VERTEBRAE, CERVICAL RIBS, LUMBAR RIBS, & CAUDAL VERTEBRAE IN FETUSES, & ALSO DECR NEONATAL SURVIVAL RATE. IT DID NOT AFFECT BEHAVIOR, LEARNING ABILITY, & FERTILITY OF OFFSPRING.PENICILLAMINE-INDUCED MYASTHENIC RESPONSES IN GUINEA PIGS WAS STUDIED. ANIMALS SHOWED EDROPHONIUM CHLORIDE-REPAIRABLE DECREMENTAL RESPONSES TO 30-HZ NERVE STIMULATION. 3 REVEALED POST-TETANIC EXHAUSTION. 11 HAD DECR MINIATURE ENDPLATE POTENTIAL AMPLITUDES, COMPARED WITH 6 CONTROLS.For more Non-Human Toxicity Excerpts (Complete) data for (D)-PENICILLAMINE (13 total), please visit the HSDB record page. |
| Populations at Special Risk | It is recommended that penicillamine not be used to treat pregnant patients with rheumatoid arthritis and that it be avoided if possible in pregnant patients with cystinuria.Patients 65 years of age or older may be more likely to develop hematologic toxicity with penicillamine. Also, elderly patients are more likely to have age-related renal function impairment, which increases the risk of adverse renal effects in patients receiving penicillamine for the treatment of rheumatoid arthritis. |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during LactationLimited information indicates that penicillamine is not detectable in breastmilk and no adverse effects have been reported among breastfed infants whose mothers were taking the drug. Copper and zinc levels in breastmilk are reduced in some mothers receiving penicillamine. Penicillamine has been used with apparent safety during nursing of several infants. Based on available data, it appears that penicillamine is acceptable to use during breastfeeding.◉ Effects in Breastfed InfantsOne woman taking penicillamine 1500 mg daily for cystinuria breastfed her infant for 3 months with no apparent adverse effects in her infant.A woman taking penicillamine in an unspecified dosage for Wilson’s disease breastfed her infant. The infant’s serum copper and zinc levels were normal. The infant fed well and developed normally.Another woman breastfed 2 infants after 2 pregnancies while being treated for Wilson's disease with penicillamine 750 mg daily. One infant had prolonged icterus that was unlikely to have been related to the penicillamine.A center in Türkiye reported 23 infants born to mothers with Wilson's disease over a 20-year period. Twenty-one were treated with penicillamine 600 mg and zinc 100 mg daily. All infants were breastfed (extent and duration not specified). One premature infant died at 3 weeks of age (maternal drug not specified), but the other infant had no apparent complications over a median of 51 months (range 13 to 105 months) of follow-up.A center in Germany reports 32 patients with Wilson's disease who became pregnant. Thirteen of the patients were taking penicillamine in dosages of 600 to 1200 mg daily. Of the 31 women who delivered a live infant, 27 of them breastfed their infants (extent not stated). Four of the infants had neonatal jaundice, but its relationship to penicillamine cannot be determined. The exact number of women who breastfed while taking penicillamine is unclear in the report.Seven patients with Wilson’s disease were taking penicillamine in dosages of 300 to 800 mg daily. Maternal reports indicate that all infants exhibited normal development.◉ Effects on Lactation and BreastmilkIn some case reports and studies, milk concentrations of copper and zinc were reduced during therapy of Wilson's disease with penicillamine.A more recent study compared copper concentration in the milk of 7 mothers taking penicillamine compared to 25 control mothers without Wilson’s disease. The copper concentration in the colostrum (0-4 days postpartum) of women treated with penicillamine was slightly higher than normal. Copper and zinc concentrations were normal in mature breastmilk (>14 days postpartum) from all mothers treated with penicillamine, despite lower copper concentrations in maternal serum. |
| Wassergefährdungsklasse (WGK) | 2 |
| Zollcode | 29309016 |
| RTECS-Nr. | YV9425000 |
| R-Sätze (R) | 36/37/38-40-20/21/22 |
| Toxizität | LD50 in rats (mg/kg): >10000 orally, >660 i.p. (Jaffe) |
| Gefahrensymbole | Xi,T,Xn |
| hazard_note | Toxic |
| Sicherheitshinweise (S) | 26-36-24/25-22 |
| Lagerklasse | 11 - Combustible Solids |
| Gefahrstoffdaten | 52-67-5(Hazardous Substances Data) |
| Gefahrenklasse | Repr. 2 |
Anwendungen & Verwendung
Beschreibung
Penicillamine is an orally bioavailable copper chelator and penicillin degradation product. It increases urinary and fecal copper excretion and decreases liver copper concentration in a rat model of copper overload when administered at 0.67 mmol/kg per day, but does not affect kidney, spleen, or brain copper levels. Penicillamine (100 mg/kg per day) dissolves copper-rich granules in hepatic lysosomes of Long-Evans cinnamon (LEC) rats, which spontaneously develop hepatic injury and acute hepatitis and have a mutation homologous to that of the human Wilson disease gene. Penicillamine has anticonvulsant and proconvulsant effects in mice when administered at 0.5 and 250 mg/kg, respectively, which are blocked by the nitric oxide synthase (NOS) inhibitors L-NAME and 7-nitroindazole . Formulations containing penicillamine have been used to treat Wilson disease, cystinuria, and active rheumatoid arthritis.
Verwenden
As a Penicillin metabolite, D-(-)-Penicillamin can be used in the treatment of Wilson’s disease, Cystinuria, Scleroderma and arsenic poisoning.