Caeruloplasmin Serum albumin^LMM Cu2+

(Metallothionein) complexes^ [Cu(H2O) 6] 2+ Zinc a2-macroglobulin Serum albumin^LMM Zn2+

Metallothionein complexes^ [Zn(H2O) 6] 2+ LMM=Low molecular mass complexes.

Table 13.6 Predominant copper complexes identified in blood plasma by computer speciation analysis.

Complex species Percentage of total Cu(II) in the low molecular

__mass fraction_

Cu(II)-Histidine- 19


Cu(II)-Histidine2* 15

Cu(II)-Histidine- 14


Cu(II)-Histidine- 11


*All these species are anions.

The analysis of the concentration and distribution of the different chemical forms (species) of a metal in a system is known as speciation. As an illustration Table 13.6 shows the principal species in which copper(II) exists in normal blood plasma. Computer simulations of metal speciation in biofluids, such as plasma, saliva, intestinal juices or milk, often run to more than 10,000 species. They require a databank of well-validated constants and analytical data and a medium-sized computer: nowadays many speciation programmes can be run on a high performance personal computer. It is important that as far as is possible computer simulations should be validated by experimental data. Many of the principles discussed earlier in this chapter have been revealed, or retrospectively checked out using computer speciation.


Some drugs are metal compounds in which the metal is essential for their desired pharmacological effect; others are ligands which exert their effects by interaction with an endogenous metal at their site of action. The use of metals as drugs can be traced back for thousands of years, for example zinc oxide unguents for wound healing or solutions of rust in acid wine for the treatment of anaemia were used in pre-Christian times. Paracelsus in the 16th Century made the general introduction of some heavy metals into the materia medica.

13.5.1 Metals as drugs

More than a dozen metals have been used as drugs during the past few hundred years, including such highly-toxic elements as arsenic, mercury and lead; Table 13.7 lists some of those which still find applications in healthcare. A few of these applications are discussed below. Bismuth in the treatment of peptic ulcer

The heavy metal bismuth has been widely used for many years for the treatment of gastric or duodenal ulceration. One of the most prescribed of these agents is a solution of tri-potassium dicitratobismuthate, containing also colourant and emollients, at pH 10. Intragastric fibre-optic colour photography suggested that the bismuth acted as a cytoprotectant by coating the ulcerated area with a precipitate which protected the raw

Table 13.7 Some metals present in pharmaceuticals administered to humans. Element__Compound__Prescribed as—and use_

Aluminium Hydroxide Silicate

Antimony Bismuth Boron Cobalt Iron Gold

Aludrox—antacid Kaolin—antidiarrhoeal Gluconate Pentostam—antilieshmaniasis

Tripotassiumcitrato De-Nol—antacid, antiulcer

Boric acid Cyanocobalamin Glycine sulphate Thiomalate

Magnesium Sulphate

Monphytol—antifungal Cobalin-H—pernicious anaemia Ferrocontin continus—iron deficiency Myocrisin—antiarthritic Epsom salts—laxative

Platinum Dichlorodiammine Cisplatin—anticancer agent Selenium Sulphide Selsun—seborrhoeic dermatitis Silver Sulphadiazine Flamazine—infected leg ulcers Tin Fluoride Toothpaste—anticaries Zinc_Sulphate_Solvazinc—proven zinc deficiency surface from further attack from the gastro- or intestinal juices. Computer speciation analysis subsequently showed that in the acid environment of the stomach the soluble charged Bi(citrate)23- is converted into insoluble precipitates of bismuth oxychloride and insoluble bismuth citrate.

Computer simulation also led to other bismuth formulations which produce cytoprotective bismuth patches over ulcers at sites having more neutral pH values. However, optimisation of such ulcer therapies is difficult because of the vagaries of ulcer origins and their response to therapy.

A new aspect to ulcer therapy with bismuth compounds was given by the discovery in the early 1980s that the intestinal bacterium Helicobacter pylori probably plays a major role in the induction of gastric ulcers, and even gastric cancer. Bismuth is itself bacteriocidal, but its effect is weak, however, combination of bismuth with antibiotics such as amoxicillin or tetracycline can raise the success rate for ulcer therapy to about 80%, i.e. by about four times that achievable with bismuth alone.

Bismuth oxide or bismuth sub-gallate are also used in combination with other agents in antiseptic preparations for the treatment of haemorrhoids. Metals as anti-cancer agents

A number of metals, such as gallium, hafnium and palladium, have been shown in animal experiments to be able to slow down the growth of tumours, but none has yet proved sufficiently effective to justify clinical trials. However, an important, but accidental, discovery in 1964 led to the development of an exciting new class of inorganic cytotoxic drugs for cancer chemotherapy. Studies of the effects of electrical currents on the growth of microorganisms led to the discovery that the simple presence of a platinum electrode in a culture, without any electric current being applied, led to severe growth disturbance. The active species were recognised to be tiny concentrations of platinum complexes which were formed in the culture. Tests of one such complex, cis-dichlorodiammineplatinum(II) (cisplatin) (13.1), in animal tumour systems showed that this was a very potent cytostatic agent.


(13.1}: cfj-dichlorodiammine platinum(II) (13,2): nitrogen mustard cisplatin

Unfortunately, it also exhibited such high general toxicity, especially nephrotoxicity, that any clinical application appeared unlikely. However, despite this disadvantage a Phase I clinical trial was commenced which confirmed the high anti-tumour effectiveness of cisplatin and showed that some of the more general toxic effects could be avoided by judicious hydration of the patient.

Cisplatin is a planar, electrically neutral complex that is able to cross cell membranes. Its cytoxic action arises by losing the two adjacent chloride ions to form platinum chelates with two nitrogens from the purine and pyrimidine bases in the desoxyribonucleic acid (DNA) chain to create an intrastrand link within the DNA that interferes with the replication of the DNA when the cell next attempts to divide. The formation of the intrastrand link by cisplatin in a single strand of the DNA contrasts to the formation of an interstrand link between the two DNA strands of the a-helix which commonly occurs with other types of alkylating agent, such as those based on nitrogen mustards (see Chapter 9). This difference in the mode of action of cisplatin and the nitrogen mustards (13.2) probably lies in the separation between the two chloride ions in the molecules. In cisplatin the distance between the two chloride ions is 0.33 nm, while the separation between the chloride ions at the ends of the arms of the nitrogen mustards is 0.80 nm; these distances correspond perfectly to the space required to form inter- and intrastrand linkages, respectively.

Cisplatin was introduced clinically in the UK in 1979 and rapidly became a first line drug for use, either alone or in combination with vinblastine or other cytoxic agents, in the treatment of ovarian and testicular cancer and also lung cancer. However, cisplatin suffers from serious disadvantages; it must be infused intravenously; it causes severe nausea and vomiting, being one of the most powerful emetics known; it causes leukopenia and renal dysfunction cannot be entirely avoided. Further, some tumours are beginning to develop resistance to the drug. Much research is being concentrated on reducing these disadvantages.

The attachment of a 1,1-dicarboxycyclobutane moiety to the diammineplatinum(II) to produce the as-(1,1-dicarboxycyclobutane)diammineplatinum(II) (13.3) derivative has removed some of these problems and introduced a second generation agent, carboplatin, into clinical use.

More recently, an orally active platinum drug has been developed. This substance bis-acetatoamminedichloro(cyclohexylamine)platinum(IV), code named JM216 (13.4), is metabolised in vivo to produce, as the main plasma metabolite, the ammine(cyclohexylamine)dichloroplatinum(II)(JM118) (13.5) derivative, which is thought to be the active cytotoxic moiety. The orally active drug JM216 is expected to enter clinical practice in the late 1990s.

Another fascinating new compound, which is still in the research phase, is trans-ammine(cyclohexylamine)dichlorodihydroxyplatinum(IV). This compound, which appears to form interstrand crosslinks in DNA, is the first trans-platinum complex to show selective anti-tumour activity in vivo. Copper and rheumatoid arthritis

This condition afflicts about 5% of the UK population and is particularly prevalent amongst the elderly. The origins of the disease are unknown but it appears to involve disturbances in the chain of reactions which control the patient's autoimmune response. Some of the weaker links in this chain appear to involve an inadequate supply of copper. This element is so widespread in nature than copper deficiency in humans is rare, however, there is much evidence to suggest that localised imbalances of tissue copper may be related to rheumatoid arthritic conditions.

The first reports that administration of low molecular mass copper complexes have a beneficial effect on rheumatoid arthritis appeared more than fifty years ago (see Sorenson 1982 in the further reading list). The mechanisms by which copper acts against rheumatic disease are still unclear although factors such as free radicals, prostaglandin balance and lysyl oxidase activity have been investigated. Further, despite many years of research, no copper-containing anti-rheumatoid arthritic drug has yet found widespread use in clinical practice. Nevertheless, a review of the many research reports concerning the role of copper complexes in vivo gives a valuable general insight into the considerations involved in the search for a metal drug. Paradoxically, the abundance of information may be a hindrance, rather than a help to our understanding and to the development of effective new copper-containing drugs.

The copper in normal human blood plasma occurs in four fractions (see Table 13.5). About 90% of the total plasma copper (~17 mmol dm-3) is complexed in a thermodynamically irreversible manner in the copper-oxidase caeruloplasmin. Some, however, is always attached to other protein-binding sites as part of a labile equilibrium between the remaining three copper fractions. These also include low molecular mass complexes and aquated ions. Apart from caeruloplasmin, albumin is by far the largest of the remaining fractions.

It is noteworthy that although the metalloprotein (caeruloplasmin) fraction is not in equilibrium with the other three fractions, in certain circumstances a steady state may be set up whereby the metal is exchanged between them. The metal uptake and release is then associated with the formation and degradation of the protein. Typically, this occurs within cells, thus metalloproteins can serve as homeostatic ion reservoirs. However, the metal in these proteins is not immediately available for other biochemical purposes. It must, therefore, be recognised that unless the metal ion fractions in labile equilibrium are rapidly replenished, a deficiency state could arise even in the presence of apparently high total concentrations of the metal ion in the tissue fluids.

Sorenson and his colleagues (1982) have reviewed the results of treatment in some 1500 arthritic patients treated with several experimental copper compounds which produced a significant reduction of inflammation. These agents exhibited anti-ulcer activity which is significant in view of the fact that gastrointestinal irritation is often a limiting factor in anti-arthritic therapy.

Sorenson also reviewed a great deal of additional evidence concerning copper complexes as anti-arthritic drugs; therefore only two pertinent findings will be mentioned here. First, copper-deficient rats are significantly more susceptible to carrageenan-induced oedema (an experimental model for arthritis) than control animals, thus establishing that a minimum level of copper in the tissues is necessary for the control of inflammation. Second, speculation about the therapeutic efficiency of copper bracelets in rheumatoid arthritis has been placed on a more scientific basis: the dissolution of copper in human sweat has been quantified, its dermal penetration and its positive beneficial effects demonstrated in a clinical trial.

Screening studies following intravenous administration of copper compounds have revealed a striking correlation between the reduction of inflammation and the amount of the metal entering the plasma compartment. The nature of the ligand attached to the copper in the administered complex does not influence the results, rather, it is the increased availability of ions per se which affords protection against the inflammation. Whatever, the mechanism of its action the inflamed tissues appear to be able to acquire copper ions from the labile equilibrium system in the plasma once the administered complex has dissociated and the metal ions have been re-distributed, proportionally, amongst the serum albumin and the naturally occurring low molecular mass ligands.

Designing copper complexes for the control of inflammation depends on a knowledge of the differences between healthy and diseased tissue at the molecular level. As has already been noted, such knowledge is still incomplete. However, whatever its true mechanism of action, the observed positive effects of copper on inflammation does suggest that a valid way forward is research aimed at increasing the supply of copper to sites of injury.

The rationale for designing rheumatoid arthritis agents which reduce inflammation in this way depends on two fundamental assumptions:

I. the therapeutic effect of copper administration arises from an increase in the total labile copper concentration in relevant body compartments, such as synovial fluid, and that

II. this increase is fostered by the formation of complexes in plasma that can diffuse across membranes into the synovial fluid.

Computer simulation predicts that the supply of copper to the tissues will be enhanced simply by increasing the labile copper concentration in the plasma itself. However, the direct injection of copper into the plasma is fraught with problems.

Intravenous injection of <1 mg dm-3 copper may produce toxic symptoms, even haemolysis of erythrocytes. Such levels may also exceed the normal binding capacity of the serum albumin, albeit perhaps only locally, leading to non-specific protein binding and an abnormal tissue distribution of the metal. Although it is possible to alleviate these undesirable effects by slow infusion, by subcutaneous injection or by using chelators to help attain equilibrium binding, such a means of administering copper would not be an appropriate regime for the routine of treatment for a disease as prevalent as rheumatoid arthritis.

Oral administration of the same compounds is a possible alternative to intravenous injection, but this route is much less effective due to the fact that 30% or less of dietary copper is absorbed into the blood stream from the gastrointestinal tract. An alternative strategy could be based on the controlled liberation of endogenous reserves of copper from the liver or other tissues.

For short-term therapy aimed at correcting a localised copper imbalance, endogenous rather than exogenous sources seem to offer a simple solution. There are three possible ways of achieving this objective:

a) by equilibrium competition for labile protein-bound copper, b) by decreasing the affinity of serum albumin for copper by allosteric effects, and c) by extracting copper from inert metalloproteins.

It has been suggested that penicillamine may act via the last mechanism in stimulating copper excretion in the treatment of patients suffering from Wilson's disease (see below).

To bypass some of the difficulties of endogenous mobilisation, attention has been drawn to the possibility of copper supplementation by dermal application. The area behind the ear has been suggested as an application site since, due to its low keratin content the skin in this region is about four times as permeable as skin elsewhere. However, the complexes selected must be able to penetrate the dermis and pass, via the lymph, into the plasma, thus similar considerations to those discussed above for intestinal absorption apply.

Dermal absorption does offer the advantage that there are no homeostatic control mechanisms to overcome. Thus, complexes need not be so specific for copper(II), nor so powerful. The risks of gastrointestinal irritation by the metal ion are also avoided. For these reasons topical application of copper complexes for the treatment of rheumatoid arthritis appears to be attractive.


13.6.1 Metal chelation in antimicrobial activity

Many microorganisms are critically dependent on one or more metals for their growth and a number of the more effective antimicrobial drugs act by denying the organism the use of such metals (Taylor and Williams 1995).

The chelating agent 8-hydroxyquinoline, oxine (13.6), has the advantage over many other antimicrobial agents of acting rapidly and also possessing fungicidal properties. It was one of the first such agents to be shown to exert its action via chelation.

The lack of antimicrobial action with derivatives in which the ligand donor groups were blocked with -O-methyl, =N-methyl, or isomeric hydroxyderivatives— suggested that the activity of oxine involved chelation. Traces of ferrous or ferric iron were shown to be required for activity and evidence suggests that the mode of action is inside the cell, or at least within the cytoplasmic membrane, since derivatives of oxine having increased hydrophilic properties and also able to chelate iron, e.g. 8-hydroxyquinoline-5-sulphonic acid, are not antibacterial. The oxine-iron complex, as a result of rearrangement of the orbitals of the Fe3+ ion, is able to catalyse the oxidation of thiol groups in lipoic acid, an essential co-enzyme required by bacteria for the oxidative decarboxylation of pyruvic acid. The importance of the lipophilic properties is illustrated by the activity of halogenated derivatives such as 5,7-diiodo-8-hydroxyquinoline and 5-chloro-8-hydroxy-7-iodoquinoline against the organisms causing bacterial dysentery.

The entry of the anti-tubercular agent isonicotinic acid hydrazide, isoniazid, (13.7), is mediated by the formation of a lipid-soluble copper chelate. The activity of other antitubercular drugs, including thiacetazone (13.8) and ethambutol (13.9) are also dependent

Synthesis Methisazone

on copper(II) chelation. The antiviral activity of methisazone (13.10) appears to arise from copper complexing to the ring carbonyl oxygen and the middle nitrogen atom of the thiosemicarbazide side chain. Such chelates have been shown to interact with nucleic acids.

The tetracyclines (13.11) constitute a group of important agents for treating systemic bacterial infections. High values for formation constants and the presence of hard basic groups, such as hydroxyl anions and tertiary amino moieties, indicate a readiness to complex Ca2+ and Mg2+. Much evidence suggests that tetracycline owes its antibacterial activity to its ability to complex Mg2+ in the bacterial cell membrane. The increased lipophilicity of the Mg2+-tetracycline complex facilitates concentration in the bacterial cell where it blocks protein biosynthesis by interfering with the binding of aminoacyl-t-RNA to ribosomal receptors.

13.6.2 Metal ion removal

In metal storage diseases, such as Wilson's disease and haematochromatosis, the symptoms can often be alleviated and the progress of the disease slowed down by treatment with a chelator with a high affinity for the metal concerned. Similarly, exogenous metal poisoning can also be treated by appropriate chelators. Removal of copper in Wilson's disease

Wilson's disease is an idiopathic condition characterised by an inability to use copper for caeruloplasmin synthesis with the result that there is massive overloading of albumin and the low molecular mass ligands with copper. Dietary copper becomes deposited in

excessive amounts in the brain, liver, eyes and other tissues causing neurological symptoms and cirrhosis of the liver leading to death relatively early in life. The progression of the disease can be markedly slowed by treatment with chelating agents such as D-penicillamine (13.12), or triethylenetetramine (TREN) (13.14). The success of D(-)-penicillamine, a hydrolysis product of some penicillins, as a copper mobilising agent in Wilson's disease, as well as in the treatment of rheumatoid arthritis, is interesting because this agent does not release copper from serum albumin. Neither does it degrade caeruloplasmin and release its vast stores of copper; it may possibly liberate the metal from liver metallothionein binding sites, but it certainly does markedly increase the urinary excretion of copper.

Although D-penicillamine does not apparently disturb serum albumin copper, it does mobilize zinc from this protein and this, together with bone marrow depression, are recognised side effects of D-penicillamine therapy. These are serious side-effects and D-penicillamine is now often replaced by the tridentate ligand triethylenetetramine(TREN) (13.14) in the treatment of Wilson's disease. Removal of iron in haematochromatosis

The massive storage of iron encountered in either primary or secondary haematochromatosis is another condition that is amenable to treatment with chelators. The secondary haematochromatosis which results from the need for repeated blood transfusions in the treatment of the genetic disease thalassaemia (sickle cell anaemia) is a major clinical problem in some tropical countries. For the last three decades the fungal siderophore desferoxamine (Desferal) (13.15) has been the only selective iron chelator available for clinical use. This is an extremely powerful ligand for the chelation of Fe3+ and it has the advantage of having little affinity for other essential metals such as copper, zinc, calcium or magnesium. Desferal forms hard acid-hard base complexes with iron in which the iron is bound more strongly than in the Fe-EDTA complex. X-ray diffraction studies suggest that the complex formed involves iron(III) bound to three -N(OH)CO- groups.

Desferal is very expensive and must be administered by slow intravenous infusion. These are serious disadvantages when the pressing clinical need is to be able to treat large numbers of young people in poor countries. There is great interest in developing inexpensive, orally active chelators for iron removal and derivatives of 3-hydroxypyridine-4-one appear to offer the desired properties. One such derivative, originally code-named L1 (13.16), has recently entered clinical practice under the name Deferiprone. This agent is able to mobilise iron from the main iron-storage protein ferritin, possibly because the molecule is small enough to enter into the so-called tunnels in the ferritin molecule and to directly chelate the ferric iron deposited there. The hydroxypyridones have also been shown to mobilise iron from the degradation product of ferritin, haemosiderin, that accumulates in the tissues of thallassaemia patients. The iron so mobilised is excreted from the body mainly via the urine. Treatment of exogenous metal poisoning

Acute or chronic poisoning by lead, or other heavy metals, remains an important clinical problem. The polyaminopolycarboxylic acid chelator ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA) (13.17) has a high affinity for lead and this agent has been shown to be a reasonably efficient chelator for lead in vivo. However, EDTA suffers from some disadvantages. First, as a charged ion ETDA4-, the form in which the drug exists in plasma, it is unable to pass through lipid membranes to reach lead deposited in cells; second EDTA is also able to complex essential ions such as Mn2+ and Zn2+ and its prolonged use can lead to a deficiency of these metals.

For some purposes EDTA is administered as the disodium salt because the tetrasodium salt is too alkaline. The disodium salt of EDTA, disodium edetate, is also used to reduce blood calcium levels in hypercalcaemia. The hard basic groups, -COO-and —NH2, of the

tetradentate EDTA form a stable water-soluble complex with the hard Ca2+ ions which is excreted via the kidney. Disodium edetate has also been used for treating limeburns on the cornea and for restoring the K+/Ca2+ balance in cardiac arrhythmias accidentally induced by digoxin. "Decorporation therapy" by regular infusions of disodium edetate is also used as an rather equivocal form of treatment for patients with atherosclerosis; the rationale being that the chelator mobilises calcium from the atherosclerotic plaques thus improving general blood flow. Some spectacular results have been claimed by protagonists of this form of therapy!

For the treatment of poisoning with lead or mercury the administration of the disodium calcium EDTA complex is preferred as this prevents the chelation and excretion of the essential endogenous calcium. An analogue of EDTA, diethylenetriaminepentaacetic acid (DTPA) (13.18) is employed in the nuclear industry for the treatment of the rare cases of human contamination with plutonium or americium.

The problem created by the charged nature of the EDTA4- and DTPA5- species which limits their transport across cell membranes and, thus, their access to intracellular metal deposits may, in theory at least, be circumvented by treatment with two ligands. If a ligand that exists in electrically neutral form in the blood, for example D-penicillamine, is administered first, followed by EDTA administration, then intracellular deposits of a metal such as lead may be mobilised and transported into the blood stream as neutral D-penicillamine complexes and then quantitatively eliminated in the urine following interaction with EDTA—such a regimen of using two chelators is known as Synergistic Chelation Therapy.

Mercury poisoning has also been treated successfully with D-penicillamine, although the N-acetyl derivative (13.13) which has a softer basic group is considered to be more effective.

Poisoning by mercury, arsenic, gold or antimony may be treated with dimercaptopropanol (dimercaprol (13.19) or British Anti-Lewisite (BAL)), one of the first chelators to be used clinically. Dimercaprol provides soft sulphydryl groups that bind these soft metals forming water-soluble complexes. Dimercaprol must be injected in an oil suspension which has a number of disadvantages, and the water-soluble derivative dimercaptopropane sulphonate, dimeval (13.20), has been used as an alternative drug for mercury and arsenic poisoning.


A prima facie case can usually be made linking a metal ion interaction with almost any drug in the pharmacopoeas and several therapeutic examples of such links have already

been discussed. However, the interaction with the metal ion is not part of the desired effect and may lead to unwanted side effects. Examples of such effects would be a drug that in the presence of an endogenous metal ion is extensively inactivated, or a substance that produces a metabolite that complexes with, and inactivates, an essential metal, or an agent designed to accelerate the excretion of an unwanted metal but which also enhances the excretion of an essential metal.

It has been postulated that thalidomide (13.21), the drug which when taken by pregnant females as a tranquilliser caused so many birth abnormalities in the 1960s, could have produced its effects of limb-shortening through hydrolysis in the embryo of the peptide-like bonds in the molecule, to produce complexing moieties that sequestered the Ca2+ ions that were essential for the normal development of the limb-buds.

Many anti-tubercular drugs chelate metal ions and, as mentioned earlier, this can enhance their biological activity by rendering them more bioavailable. However, whether such metal chelation is a characteristic of their activity or not, the administration of a ligand drug is likely to interfere with normal trace element behaviour. Such interactions need to be characterized and quantified lest topping-up therapy is necessary.

Ethambutol ((+)-2,2'-ethanediyldiimino)-bis-1-butanol) (13.9), an important antitubercular drug, is one such example. While it has been postulated that the mode of action of ethambutol may involve the formation of a ternary complex involving copper(II) ions and RNA, clinical studies have shown that it does lead to an increase in urinary zinc excretion.

Solution studies have been used to measure the formation constants for the complexing of ethambutol and its principal metabolite, 2,2'-(ethanediyldiimino)-bis-1-butane carboxylic acid (EDBA), with a range of metal ions essential to humans. Insertion of these data into a computer simulation of the interactions in blood plasma and showed that a dose of 25 mg ethambutol/kg body weight, which produces an EDBA concentration of 1.25x 10-6, raised the concentrations of low molecular mass zinc complexes by up to one third, the new complex Zn-EDBA0 being electrically neutral. However, up to ten times this dose of ethambutol has no effect on

13.7.1 Metal ion sequestration by a metabolite

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