D-Penicillamine: the State of the Art in Humans and in Dogs from a Pharmacological and Regulatory Perspective
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antibiotics Review D-Penicillamine: The State of the Art in Humans and in Dogs from a Pharmacological and Regulatory Perspective Michela Pugliese 1,† , Vito Biondi 1,† , Enrico Gugliandolo 1 , Patrizia Licata 1, Alessio Filippo Peritore 2 , Rosalia Crupi 1,* and Annamaria Passantino 1 1 Department of Veterinary Science, University of Messina, 98166 Messina, Italy; [email protected] (M.P.); [email protected] (V.B.); [email protected] (E.G.); [email protected] (P.L.); [email protected] (A.P.) 2 Department of Chemical, Biological, Pharmaceutical, and Environmental Science, University of Messina, 98168 Messina, Italy; [email protected] * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Chelant agents are the mainstay of treatment in copper-associated hepatitis in humans, where D-penicillamine is the chelant agent of first choice. In veterinary medicine, the use of D- penicillamine has increased with the recent recognition of copper-associated hepatopathies that occur in several breeds of dogs. Although the different regulatory authorities in the world (United States Food and Drugs Administration—U.S. FDA, European Medicines Agency—EMEA, etc.) do not approve D-penicillamine for use in dogs, it has been used to treat copper-associated hepatitis in dogs since the 1970s, and is prescribed legally by veterinarians as an extra-label drug to treat this disease and alleviate suffering. The present study aims to: (a) address the pharmacological features; (b) outline the clinical scenario underlying the increased interest in D-penicillamine by overviewing Citation: Pugliese, M.; Biondi, V.; Gugliandolo, E.; Licata, P.; Peritore, the evolution of its main therapeutic goals in humans and dogs; and finally, (c) provide a discussion A.F.; Crupi, R.; Passantino, A. on its use and prescription in veterinary medicine from a regulatory perspective. D-Penicillamine: The State of the Art in Humans and in Dogs from a Keywords: D-penicillamine; humans; dog; copper-associated hepatitis; prescription Pharmacological and Regulatory Perspective. Antibiotics 2021, 10, 648. https://doi.org/10.3390/ antibiotics10060648 1. Introduction Despite its name’s similarity to the widely known antibiotic penicillin, D-penicillamine Academic Editor: Lingli Huang (DPA) is a byproduct of penicillin without any antibiotic properties [1]. It is a known chelating agent, a chemical compound used to trap or remove heavy metals, such as Received: 30 March 2021 copper, lead, iron, and mercury, from the body; moreover, DPA also showed positive Accepted: 26 May 2021 immunomodulatory and antifibrotic capacities [2–5]. Published: 28 May 2021 Penicillamine, also named D-b, b-dimethylcysteine, was firstly classified as a degrada- tion product of penicillin [6], and chemically is a structural analog of cysteine, with two Publisher’s Note: MDPI stays neutral methyl groups in place of the two hydrogen atoms linked to the second carbon atom of with regard to jurisdictional claims in published maps and institutional affil- cysteine [7]. For its structure, penicillamine shows similar properties to cysteine (Cys) and, iations. for this reason, it is classified as a nonproteinogenic amino acid containing a thiol group [8]. Penicillamine is also considered a trifunctional amino acid, in which an amino group and a carboxyl group are attached to one carbon atom, and a sulfhydryl and two methyl groups to a second (Figure1)[ 7]. The three functional groups in penicillamine undergo character- istic chemical reactions and change in their ability to participate in acid–base equilibria, Copyright: © 2021 by the authors. nucleophilic addition and displacement, combination with various metals, oxidation, and Licensee MDPI, Basel, Switzerland. free radical transformations [9]. Two are the enantiomers recognized: D and L isomers. In This article is an open access article particular, D isomer is the only one that can be utilized in clinical practice, although the L distributed under the terms and conditions of the Creative Commons isomer is characterized by excessive toxicity [1]. Attribution (CC BY) license (https:// In humans, DPA, due to its metal chelating properties, is used to treat several dis- creativecommons.org/licenses/by/ eases, including Wilson’s disease [10], heavy metal intoxication [11], cystinuria [12], and 4.0/). rheumatoid arthritis [13]; at the same time, DPA’s chelating ability is also used in veterinary Antibiotics 2021, 10, 648. https://doi.org/10.3390/antibiotics10060648 https://www.mdpi.com/journal/antibiotics Antibiotics 2021, 10, 648 2 of 15 medicine, and it is used in the treatment of liver disease caused by the accumulation of abnormal storage of copper [14]. In fact, it is considered the initial treatment of choice for most dogs with copper-associated hepatitis, including those with clinical illness and Antibiotics 2021, 10, 648 those with moderate to severe hepatic histopathologic abnormalities [15]. Furthermore, 2 of 15 this veterinary medicine is also used for the long-term oral treatment of lead, or cadmium, and mercury poisoning, or cysteine urolithiasis [16,17]. Figure 1. Figure 1.Structure Structure of D-penicillamine. of D-penicillamine. Though DPA remains an effective drug for many dogs with copper-associated hepati- tis, thereIn ishumans, a limitation DPA, to its usedue due to toits scarce metal availability chelating for theproperties, reason that is it used is marketed to treat several dis- onlyeases, for including humane use Wilson’s [14]. disease [10], heavy metal intoxication [11], cystinuria [12], and rheumatoidThis lack of arthritis animal equivalent [13]; at the product same results time, in veterinariansDPA’s chelating using this ability drug outsideis also used in veteri- of the authorized conditions of use, detailed in its summary of product characteristics to treatnary disease medicine, and alleviate and it sufferingis used in [14 the,18– 20treatment]. of liver disease caused by the accumulation of abnormalGiven that DPAstorage has increasedof copper in [14]. recent In years fact, for it its is effectiveness considered in the the initial treatment treatment of of choice copper-associatedfor most dogs hepatopathies,with copper-associated decreasing hepatic hepatitis, copper concentrationincluding those and diminishing with clinical illness and thethose grade with of inflammation, moderate theto authors:severe (a)hepatic address histop the pharmacologicalathologic abnormalities features; (b) outline [15]. Furthermore, the clinical scenario underlying the increased interest on DPA, by overviewing the evolution ofthis its mainveterinary therapeutic medicine goals in is humans also used and for dogs; the and long-term finally, (c) provideoral treatment a discussion of lead, on or cadmium, itsand use mercury and prescription poisoning, in veterinary or cysteine medicine urolithiasis from a regulatory [16,17]. perspective. Though DPA remains an effective drug for many dogs with copper-associated hepa- 2.titis, Absorption, there is Distribution,a limitation Metabolism to its use anddue Excretion to scarce (ADME) availability for the reason that it is mar- ketedPenicillamine only for humane is absorbed use rapidly [14]. from the gastrointestinal tract, with an oral bioavail- ability between 40 and 70%. Literature studies show that its availability is significantly reducedThis when lack taken of withanimal iron supplements,equivalent product antacids, orresults food; in in fact, veterinarians peak concentrations using this drug out- inside blood of arethe achieved authorized in 1–3 conditions h after administration of use, deta [21iled]. in its summary of product characteristics to treatIn contrast disease to cysteine,and allevi penicillamineate suffering is quite [14,18–20]. resistant to attacks by cysteine deoldhy- drase orGiven L-amino that acid DPA oxidase, has soincreased it is stable inin recent vivo. Almost years all for penicillamine its effectiveness is degraded in the treatment of by the liver and its metabolites have been identified in both urine and feces [22]. Once penicillaminecopper-associated is ingested, hepatopathies, it transforms into decreasing disulfides [21 hepatic,22], inorganic copper sulphates, concentration N-acetyl- and diminish- D-penicillamine,ing the grade andof inflammation, S-methyl-D-penicillamine the authors: [23]. (a) address the pharmacological features; (b) outlineAmong the metabolites, clinical scenario the disulfides underlying are the most the important,increased since interest they bindon DPA, to albumin, by overviewing the andevolution this binding of its is responsiblemain therapeutic for the slow goals elimination in humans of the drugand fromdogs; plasma and finally, [24]. It (c) provide a wasdiscussion demonstrated on its that use 80% and of penicillamineprescription in in plasma veterinary is protein medicine bound, whereas from a 6regulatory % is perspec- found in its free form, and the remaining metabolites account for 14 % [25]. Moreover, s-methyl-D-penicillaminetive. is further oxidized into sulfoxide or sulfone. Patients who are poor sulfoxidizers have demonstrated an increased rate of immunologically mediated toxicity2. Absorption, from penicillamine Distribution, [26]. It Metabolism was suggested and that penicillamineExcretion (ADME) is slowly released from deep tissues and skin [27]. Penicillamine is considered a chelating agent for lead, copper,Penicillamine iron, and mercury is absorbed [16,17,28]. rapidly from the gastrointestinal tract, with an oral bioa- vailability