D-Valine, 3-mercapto-, labeled with deuterium

149.21 g/mol

149.05104977 g/mol

200-148-8

GNN1DV99GX

DTXSID6037069

C729

FINE, WHITE OR PRACTICALLY WHITE, CRYSTALLINE POWDER

M - Musculo-skeletal system

64.3 Ų

-1.78 (LogP)

198.5 °C|202-206 °C

0.74 M|CRYSTALS; DECOMP 177.5 °C; SPECIFIC OPTICAL ROTATION: -63 DEG @ 25 °C/D (1N SODIUM HYDROXIDE); HYGROSCOPIC; FREELY SOL IN WATER, SOL IN ETHANOL. /D-PENICILLAMINE HYDROCHLORIDE/|FREELY SOL IN WATER; SLIGHTLY SOL IN ALC; INSOL IN ETHER, CHLOROFORM.

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/

SLIGHT CHARACTERISTIC ODOR

SLIGHTLY BITTER

1.8

CRYSTALS; DECOMP 201 °C; PK VALUES: CARBOXYL 1.8, ALPHA-AMINO 7.9, BETA-THIOL 10.5 /DL-PENICILLAMINE/|CRYSTALS; DECOMP 145-148 °C /DL-PENICILLAMINE HYDROCHLORIDE/|CRYSTALS; MP 190-194 °C; SPECIFIC OPTICAL ROTATION: +63 DEG @ 25 °C/D (IN N SODIUM HYDROXIDE). /L-PENICILLAMINE/|Decomposes at 178 °C

RELATIVELY STABLE IN BOTH LIGHT & AIR.|AQ SOLN IS COMPARATIVELY STABLE @ PH 2-4

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 amended; 21 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.

HUSKISSON EC; EUR J RHEUMATOL INFLAMMATION 3 (2): 156 (1979); REVIEW ARTICLE ON THE RENAL TOXICITY OF PENICILLAMINE.|JELLUM E, MUNTHE E; NAT SULFUR CMPD, (PROC INT MEET) 3RD: 375 (1980); CLINICAL EFFECTS OF PENICILLAMINE IN THE TREATMENT OF RHEUMATOID ARTHRITIS ARE DISCUSSED.|Howard-Lock HE et al; D-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 DA; D-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.

|Warning|H315 (94%): Causes skin irritation [Warning Skin corrosion/irritation]|P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 50 companies from 9 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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.

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.

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.

>80% (bound to plasma proteins)

For treatment of Wilson's disease, cystinuria and active rheumatoid arthritis.|FDA Label

Penicillamine is chelating agent used to decrease copper stores in Wilson disease, which also has immunomodulatory activity in rheumatic diseases such as rheumatoid arthritis, scleroderma and systemic lupus erythematosus. Penicillamine is capable of causing hypersensitivity reactions, some of which are accompanied by liver injury which is typically cholestatic.

Antirheumatic Agents

Antidotes; Antirheumatic Agents; Chelating Agents|THE D ISOMER IS USED CLINICALLY, ALTHOUGH THE L ISOMER ALSO FORMS CHELATION COMPLEXES. PENICILLAMINE IS EFFECTIVE CHELATOR OF COPPER, MERCURY, ZINC, & LEAD & PROMOTES EXCRETION OF THESE METALS IN URINE.|THERE IS SOME PROMISE IN TREATMENT OF RHEUMATOID ARTHRITIS WITH PENICILLAMINE. ... BENEFICIAL EFFECT IS SEEN ONLY AFTER SEVERAL WK OF TREATMENT, & ARTHRITIC SYMPTOMS RETURN IF DRUG IS WITHDRAWN PREMATURELY.|PENICILLAMINE HAS BECOME ESTABLISHED IN TREATMENT OF CYSTINURIA & ASSOC NEPHROLITHIASIS. IN DOSE OF 30 MG/KG/DAY, IT LOWERS OR ELIMINATES URINARY CYSTINE & PREVENTS FURTHER STONE DEVELOPMENT.|For more Therapeutic Uses (Complete) data for (D)-PENICILLAMINE (11 total), please visit the HSDB record page.

VET: USE IN PREGNANCY IS CONTRAINDICATED BECAUSE OF ITS CHELATING EFFECT ON TRACE METALS.|CROSS SENSITIVITY BETWEEN PENICILLIN & PENICILLAMINE DOES NOT ALWAYS OCCUR; THEREFORE, PENICILLAMINE CAN BE GIVEN CAUTIOUSLY TO PATIENTS WHO ARE HYPERSENSITIVE TO PENICILLIN.|CAREFUL EXAM OF SKIN, AS WELL AS URINALYSIS, DIFFERENTIAL & WHITE BLOOD CELL COUNTS, DIRECT PLATELET COUNTS, & HEMOGLOBIN DETERMINATION SHOULD BE PERFORMED.|EXPTL, TOXIC EFFECTS IN RATS GIVEN HIGH DOSES OF PENICILLAMINE RESEMBLE THOSE SEEN IN PYRIDOXINE DEFICIENCY, & EFFECTS ARE REVERSED BY FEEDING PYRIDOXINE. IN HUMAN BEINGS, PYRIDOXINE ANTAGONISM IS READILY DEMONSTRATED WITH L & DL FORMS, BUT RARELY WITH D FORM. ... INCR URINARY EXCRETION OF XANTHURENIC ACID & KYNURENINE.|For more Drug Warnings (Complete) data for (D)-PENICILLAMINE (11 total), please visit the HSDB record page.

Penicillamine is a chelating agent used in the treatment of Wilson's disease. It is also used to reduce cystine excretion in cystinuria and to treat patients with severe, active rheumatoid arthritis unresponsive to conventional therapy. Penicillamine is used as a form of immunosuppression to treat rheumatoid arthritis. Penicillamine inhibits macrophages, decreases IL-1 and the number of T-lymphocytes, and prevents collagen cross linkage. In Wilson's disease it binds copper, allowing it to be eliminated in the urine.

Drugs that are used to treat RHEUMATOID ARTHRITIS. (See all compounds classified as Antirheumatic Agents.)|Chemicals that bind to and remove ions from solutions. Many chelating agents function through the formation of COORDINATION COMPLEXES with METALS. (See all compounds classified as Chelating Agents.)|Agents counteracting or neutralizing the action of POISONS. (See all compounds classified as Antidotes.)

rapidly but incompletely|Excretion is mainly renal, mainly as disulfides.|HUMAN SUBJECTS SUFFERING FROM WILSON'S DISEASE, RAPIDLY ABSORBED ORAL DOSE OF (35)S DL-PENICILLAMINE. PLASMA CONCN OF (35)S PEAKED WITHIN 60 MIN. (35)S WAS RAPIDLY EXCRETED, ALMOST COMPLETELY IN 24 HR URINE WHERE 73% OF ADMIN (35)S ... RECOVERED. THERE WAS INTERSUBJECT VARIATION IN EXTENT OF BINDING ... BY PLASMA PROTEINS. /DL-PENICILLAMINE/|FROM METABOLIC POINT OF VIEW, D-PENICILLAMINE IS VIRTUALLY INERT, & THIS OBSERVATION IS COMPATIBLE WITH FACT THAT EXTRACELLULAR WATER MAKES UP MAIN DISTRIBUTION VOL FOR D-PENICILLAMINE.|PENICILLAMINE IS WELL ABSORBED (40% to70%) FROM GI TRACT &, THEREFORE, HAS DECIDED ADVANTAGE OVER OTHER CHELATING AGENTS. PEAK CONCN IN BLOOD ARE OBTAINED BETWEEN 1 AND 3 HR AFTER ADMINISTRATION. ... /IT/ IS SOMEWHAT RESISTANT TO ATTACK BY CYSTEINE DESULFHYDRASE OR L-AMINO ACID OXIDASE. AS A RESULT ... IS RELATIVELY STABLE IN VIVO. ... HEPATIC BIOTRANSFORMATION IS RESPONSIBLE FOR MOST OF THE DEGRADATION OF PENICILLAMINE, AND VERY LITTLE IS EXCRETED UNCHANGED. METABOLITES ARE FOUND IN BOTH URINE AND FECES.|The effects of chelating agents (citric acid, tartaric acid, penicillamine and ethylenediaminetetraacetic acid) and cysteine on the absorption of mercuric chloride were investigated in rats. Perfusion of the small intestine showed that the chelating agents and cysteine decreased the absorption of mercuric chloride depending on their stability of constants wtih Hg2+, under the predominant conditions of water absorption and secretion. The difference in absorption of mercuric chloride between both conditions was inversely correlated with their logarithmic stability constant values. These agents decreased the transport of mercuric chloride through the everted intestinal wall and the uptake of mercuric chloride by the intestinal brush border membrane in a similar manner. From these results, it is suggested that the chelating agents and cysteine decrease the absorption of mercuric chloride through the pores of the brush border membrane due to th solvent drag effect.|For more Absorption, Distribution and Excretion (Complete) data for (D)-PENICILLAMINE (7 total), please visit the HSDB record page.

Hepatic|The transformation of D-penicillamine was studied in orally and iv dosed rats and in human plasma in vitro. In each case, low molecular weight metabolites (previously identified as disulfides) and a mixed disulfide between D-penicillamine and albumin (D-penicillamine-protein) formed. The rates of D-penicillamine elimination, other than through protein conjugation, were comparable in the rat groups to the rate of oxidation to low molecula weight metabolites in vitro. The rates of transformation to D-penicillamine protein were also comparable in the in vitro preparations and in orally treated rats. These qualitative and quantitative similarities suggest blood plasma may be an important site of transformation in vivo. Extracellular oxidation of D-penicillamine may be linked to its antirheumatic action, either through reduction of oxygen species or through formation of D-penicillamine protein disulfides at surfaces of mononuclear leukocytes.

1 hour

Penicillamine is a chelating agent recommended for the removal of excess copper in patients with Wilson's disease. From in vitro studies which indicate that one atom of copper combines with two molecules of penicillamine. Penicillamine also reduces excess cystine excretion in cystinuria. This is done, at least in part, by disulfide interchange between penicillamine and cystine, resulting in formation of penicillamine-cysteine disulfide, a substance that is much more soluble than cystine and is excreted readily. Penicillamine interferes with the formation of cross-links between tropocollagen molecules and cleaves them when newly formed. The mechanism of action of penicillamine in rheumatoid arthritis is unknown although it appears to suppress disease activity. Unlike cytotoxic immunosuppressants, penicillamine markedly lowers IgM rheumatoid factor but produces no significant depression in absolute levels of serum immunoglobulins. Also unlike cytotoxic immunosuppressants which act on both, penicillamine in vitro depresses T-cell activity but not B-cell activity.|The rationale for ... use in cyctinuria is that penicillamine forms a relatively soluble disulfide compound with cysteine through a disulfide interchange mechanism and thereby decr the formation of cystine containing renal stones.|Penicillamine chelates mercury, lead, copper, iron, and probably other heavy metals to form stable, soluble complexes that are readily excreted in the urine.|The mechanism of action of penicillamine in rheumatoid arthritis is not known, but may involve improvement of lymphocyte function. It markedly reduces IgM rheumatoid factor and immune complexes in serum and synovial fluid, but does not significantly lower absolute concentrations of serum immunoglobulins. In vitro, penicillamine depresses T-cell but not B-cell activity. However, the relationship of these effects to the activity of penicillamine in rheumatoid arthritis is not known.|Antiurolithic (cystine calculi) Penicillamine combines chemically with cystine (cysteine-cysteine disulfide) to form penicillamine cysteine disulfide, which is more soluble than cystine and is readily excreted. As a result, urinary cystine concentrations are lowered and the formation of cystine calculi is prevented. With prolonged treatment, existing cystine calculi may be gradually dissolved.

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.

beta,beta Dimethylcysteine

Penicillamine is available in capsules containing 125 or 250 mg (CUPRIMINE) or as 250 mg tablets (DEPEN).

/D-PENICILLAMINE/ IS THE MOST CHARACTERISTIC DEGRADATION PRODUCT OF PENICILLIN TYPE ANTIBIOTICS.|D-ISOMER IS NATURAL FORM.

A spectrophotometric method for the determination of micro amt of D-penicillamine is described, based on the oxidn of the D-penicillamine by Fe(III) in the presence of o-phenanthroline, with which the Fe(II) resulted forms a ferroin complex. The latter exhibits an absorption max at 510 nm with an apparent molar absorptivity of 1.01X10+4 l/mol/cm and a Sandell sensitivity of 14.7 ng/cu cm (for log I0/I = 10-3), both referred to the drug analyzed. The optimum concn range is 2.0-15.0 ug/ml of D-penicillamine. The regression equation is A = 7.46 X10-3 C - 3.70X10-2 with a correlation coefficient of 0.9997 (n = 28).

A rapid and precise HPLC assay for both N-acetylcysteine and penicillamine, in blood samples is described using selective reductive electrochemical detection and a high-efficiency C18 reversed-phase column. The use of an internal std compensated for changes in detector responses during a run for variable sample recovery. The detection limits for N-acetylcysteine and penicillamine were 25 and 10 ng/ml, respectively, using 500 ul blood samples. Reproducibility of measurement of both thiols was excellent. This method allows routine monitoring of blood levels and pharmacokinetic studies with N-acetylcysteine and penicillamine.|ELISA methods for determination of antibodies to drugs, formed as a result of drug allergies, are described, with emphasis on determination of antibodies to penicillamine.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients