Cellular immunological responses are stimulated by penicillamine (D-(-)-penicillamine) (5 mg; 7 days; CD4+ and CD+ splenocytes) [3].

Serum free copper concentrations are raised by penicillamine (D-(-)-penicillamine) (200 mg/kg; ig; daily for 3, 10, and 14 days; tx mice and DL mice) [1]. In the brains of tx mice and DL mice, penicillamine (200 mg/kg; ig; daily for 3, 10, and 14 days) enhances the expression of CTR1 and ATP7A mRNA [1]. Penicillamine causes oxidative stress in the central nervous system when administered intraperitoneally (i.g., 200 mg/kg; tx mice and DL mice) for 3, 10, and 14 days [1]. Penicillamine has a binaural impact on epileptic convulsions when administered intraperitoneally (0.1–250 mg/kg) to male NMRI mice once for 90 minutes [2]. Small dosages of penicillamine (5 mg/kg; intravenous injection; once daily for 8 weeks; male BN rats) can stop autoimmunity from developing [3].

Western Blot Analysis[3]
Cell Types: CD4+ and CD+ splenocytes
Tested Concentrations: 5 mg
Incubation Duration: 7 days
Experimental Results: IL-4 and IFN-γ mRNA expression increased after high-dose treatment, and expression in CD4+ and CD+ splenocytes remained Keep it high.

Animal/Disease Models: Toxic lactation mutant mice (tx mice) and DL mice [1]
Doses: 200 mg/kg
Route of Administration: po (oral gavage); one time/day for 3, 10 and 14 days
Experimental Results: tx on day 3 Free copper concentrations increased in mouse serum.

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Animal/Disease Models: Toxic lactation mutant mice (tx mice) and DL mice [1]
Doses: 200 mg/kg
Route of Administration: po (oral gavage); one time/day for 3, 10 and 14 days
Experimental Results: ATP7A mRNA expression Increased by 4 times. CTR1 mRNA expression increased 6.9-fold in the cortex and 9.1-fold in the basal ganglia of tx mice.

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Animal/Disease Models: Toxic lactation mutant mice (tx mice) and DL mice [1]
Doses: 200 mg/kg
Route of Administration: po (oral gavage); one time/day for 3, 10 and 14 days
Experimental Results: Via nitric oxide /NMDA pathway increases MDA concentration and decreases GSH/GSSG ratio.

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Animal/Disease Models: Male NMRI mouse [2]
Doses: 0.1, 0.5, 1, 10, 100, 150 and 250 mg/kg
Route of Administration: intraperitoneal (ip) injection; once for 90 minutes
Experimental Results: Low dose (0.5 mg/kg) It has anticonvulsant effects, and high dos

Absorption, Distribution and Excretion
Absorption is rapid but incomplete. It is primarily excreted via the kidneys, mainly as disulfides. In subjects with Wilson's disease, (35)S DL-penicillamine was rapidly absorbed after oral administration. Peak plasma (35)S concentrations were reached within 60 minutes. (35)S was rapidly excreted, almost entirely excreted in 24-hour urine, with 73% of the administered (35)S being recovered. The degree of binding of plasma proteins to (35)S varied among individuals. DL-penicillamine is almost inert from a metabolic perspective, a finding consistent with the fact that extracellular fluid constitutes the primary volume of distribution for DL-penicillamine. Penicillamine is well absorbed in the gastrointestinal tract (40% to 70%), thus offering a significant advantage over other chelators. Peak plasma concentrations were reached 1 to 3 hours after administration. …It exhibits some resistance to attack by cysteine desulfurases or L-amino acid oxidases. Therefore…it is relatively stable in vivo. Hepatic biotransformation is the primary pathway for penicillamine degradation, with only a very small amount excreted unchanged. Metabolites are present in urine and feces. This study investigated the effects of chelating agents (citric acid, tartaric acid, penicillamine, and EDTA) and cysteine on mercuric chloride absorption in rats. Small intestinal perfusion experiments showed that, under conditions dominated by water absorption and secretion, chelating agents and cysteine reduced mercuric chloride absorption, and the degree of reduction depended on their stability constants with Hg2+. The difference in mercuric chloride absorption under the two conditions was negatively correlated with their logarithmic stability constant values. These drugs similarly reduced the transport of mercuric chloride through the everted intestinal wall and its absorption through the brush border membrane. These results suggest that chelating agents and cysteine reduce mercuric chloride absorption through the brush border membrane pores through a solvent drag effect. For more complete data on the absorption, distribution, and excretion of (D)-penicillamines (7 in total), please visit the HSDB record page.

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Metabolism/Metabolites
Liver
The transformation of D-penicillamine was investigated in rats administered orally and intravenously, as well as in human plasma in vitro. In all cases, low-molecular-weight metabolites (previously identified as disulfides) and mixed disulfides between D-penicillamine and albumin (D-penicillamine-protein) were formed. Except for the protein-binding pathway, the elimination rate of D-penicillamine in rats was comparable to the rate of oxidation to low-molecular-weight metabolites in vitro. The rate of conversion of D-penicillamine to protein in rats after in vitro and oral administration was also comparable. These qualitative and quantitative similarities suggest that plasma may be an important site of transformation in vivo. The extracellular oxidation of D-penicillamine may be related to its antirheumatic effects, possibly through the reduction of reactive oxygen species or the formation of D-penicillamine-protein disulfide bonds on the surface of monocytes.

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Biological Half-Life
1 hour

Interactions
Adding penicillamine to a drug treatment regimen typically allows for a reduction in the dosage of other anti-inflammatory drugs (especially corticosteroids). Because penicillamine inhibits pyridoxal-dependent enzymes, pyridoxine should be administered concurrently at a dose of 10-25 mg/day. Concomitant use of penicillamine with 4-aminoquinoline drugs, myelosuppressants…or gold preparations, or immunosuppressants (excluding glucocorticoids) may increase the risk of serious hematologic and/or renal adverse reactions. Concomitant use with 4-aminoquinoline drugs may increase the risk of serious skin reactions. For more complete data on (D)-penicillamine (a total of 8 interactions), please visit [insert link here]. HSDB record page.

[1]. Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice. PLoS One. 2012;7(5):e37709.

[2]. Effects of D-penicillamine on pentylenetetrazole-induced seizures in mice: involvement of nitric oxide/NMDA pathways. Epilepsy Behav. 2014 Oct;39:42-7.

[3]. Tolerance induced by low dose D-penicillamine in the brown Norway rat model of drug-induced autoimmunity is immune-mediated. Chem Res Toxicol. 2004 Jan;17(1):82-94.

[4]. Penicillamine revisited: historic overview and review of the clinical uses and cutaneous adverse effects. Am J Clin Dermatol. 2013 Jun;14(3):223-33.

Therapeutic Uses
Antidote; Antirheumatic drug; Chelating agent The D-isomer is used clinically, but the L-isomer can also form chelates. Penicillamine is an effective chelator of copper, mercury, zinc, and lead, and promotes the excretion of these metals in urine. Penicillamine shows potential in the treatment of rheumatoid arthritis. …Efficacy only becomes apparent after several weeks of treatment; if the drug is discontinued too early, arthritis symptoms will recur. Penicillamine has become a commonly used drug for the treatment of cystinuria and related kidney stones. A daily dose of 30 mg/kg body weight can reduce or eliminate urinary cystine and prevent further stone formation. For more complete data on the therapeutic uses of (D)-penicillamine (11 in total), please visit the HSDB record page. Drug Warnings Veterinary drug: Contraindicated during pregnancy due to its chelating effect on trace metals.
Cross-sensitivity reactions do not always exist between penicillin and penicillamine; therefore, patients allergic to penicillin should use penicillamine with caution.
A thorough skin examination and urinalysis, white blood cell differential count, direct platelet count, and hemoglobin determination should be performed.
Experiments have shown that toxic reactions in rats after administration of high doses of penicillamine are similar to pyridoxine deficiency, and these reactions can be reversed by pyridoxine supplementation. In humans, L- and DL-type penicillamines readily exhibit pyridoxine antagonism, but D-type penicillamines rarely show this effect. ...Increases the excretion of urinary xanthuric acid and kynurenine.
For more complete data on drug warnings for (D)-penicillamine (11 in total), please visit the HSDB record page.

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Pharmacodynamics
Penicillamine is a chelating agent used to treat Wilson's disease. It is also used to reduce cystine excretion in patients with cystinuria and to treat patients with severe active rheumatoid arthritis who are unresponsive to conventional therapies. Penicillamine is used as an immunosuppressant to treat rheumatoid arthritis. It inhibits macrophages, reduces the number of IL-1 and T lymphocytes, and prevents collagen cross-linking. In Wilson's disease, it binds to copper, allowing it to be excreted in the urine.

C5H11NO2S

149.21

149.051

52-67-5

DL-Penicillamine;52-66-4;Penicillamine-d3

5852

White to off-white solid powder

1.2±0.1 g/cm3

251.8±35.0 °C at 760 mmHg

210 °C (dec.)(lit.)

106.1±25.9 °C

0.0±1.1 mmHg at 25°C

1.528

0.93

3

4

2

9

124

1

CC(C)([C@H](C(=O)O)N)S

VVNCNSJFMMFHPL-VKHMYHEASA-N

InChI=1S/C5H11NO2S/c1-5(2,9)3(6)4(7)8/h3,9H,6H2,1-2H3,(H,7,8)/t3-/m0/s1

(2S)-2-amino-3-methyl-3-sulfanylbutanoic acid

Penicillamine; D-Penicillamine; Penicillamine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~125 mg/mL (~837.75 mM)
DMSO : ~1.43 mg/mL (~9.58 mM)

Solubility in Formulation 1: 100 mg/mL (670.20 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)