摘要:
1974 1849Thermodynamic Considerations in Co-ordination. Part X1X.I /n vitroStudies of Complexing Equilibria involved in Oral Iron(ii) TherapyBy J . Neil Cape, Diana H. Cook, and David R. Williams,' Department of Chemistry, University of St. Andrews,St. Andrews KY16 9STFormation constants are reported for adding protons and iron(r1) ions to ligands currently in use as oral iron prepara-tions (ascorbate, fumarate, and succinate). These constants have been used in computer models of solutionequilibria in the small intestine in order to establish that iron(l1)-absorption-promoting ligands preferably ( i ) havecharge 2-, ( i i ) form uncharged 1 : 1 complexes, and (iii) might be low-molecular-weight polymers. These factorssuggest a series of additional ligands that conceivably could possess improved absorption-promotion characteris-tics. Formation constantsfor these ligand-iron(rr) complexes have been determined and the concentration distribu-tion of these complexes over a range of physiological pH values computed, the most promising ligands beinggalacturonate and malate.HUMAN beings contain ca.5 g of iron and this quantity being partly absorbed in the duodenum and j e j ~ n u r n . ~remains constant throughout adult life, reflecting a The extent of this small intestinal absorption is influencedfine balance between that excreted and absorbed. by diet, efficiency of the columnar epithelial absorption-Imbalances can result in iron-deficiency diseases or in excretion mechanism, and anions associated with thehemosider~sis.~>~ The former condition is usually iron(r1) ion in the administered dose.treated by oral administration of salts of iron(xI), these Unfortunately, oral administration of iron(r1) saltsDalton, 1074, 1186.4 G. W. Bates and P. Saltman, An Introduction to Bio-1 Part XVIII, M. D. rl'alker and D. R. Williams, J.C.S.2 M. E. Conrad and W. H. Crosby, Blood, 1963, 22, 406.S. Granick, Ann. New Yovk Acad; Med., 1954, 30, 81.inorganic Chemistry,' ed. D. R. Williams, in preparation1850 J.C.S. Daltonhas several disadvantages: (i) iron(x1) ions are only5-10y0 absorbed in normal human beings (iron-deficient patients can absorb up to 29%); (ii) un-absorbed iron causes gastrointestinal distress (28% ofpatients on iron therapy report side effects); and(iii) deaths from overdoses of iron(I1) sulphate occuroccasionally.Thus the upper limit to iron(r1) sulphatetherapy is the extent of gastrointestinal irritation thatthe patient can tolerate. A wide variety of ligands(mainly carboxylic acids and carbohydrates) has beenused in place of sulphate either to increase the pro-portion of iron@) absorbed in the small intestine or todecrease the extent of gastrointestinal irritation (bothconcepts having the effect of increasing the maximumconcentration of oral-iron therapy possible) .697All these preparations are administered orally assolids and this study reports solution equilibriumstudies on the more promising systems (i) to expressintestinal iron-ligand equilibria in terms of formation(Found: C, 41.3; H, 4-6.Calc. for C,H,O,: C, 40.9;H, 4.55%); fumaric (B.D.H.), n1.p. 297-299 "C (lit.300.2 "C) (Found: C, 41.45; H, 3.35. Calc. for C4H404:C, 41.4; H, 3.45%) ; galacturonic (B.D.H., citrus origin),m.p. 156-157 "C [lit. 156-160 "C (decomp.)] (Found:c , 34.15; H, 5-80. Cak. for C,H,,O,: c , 33.95; H, 5.70%) ;and succinic (B.D.H., AnalaR), m.p. 187.5 "C (lit. 188 "C)(Found: C, 40.8; H, 5.20. Calc. for C,H,04: C, 40.7;H, 5.100,&). Other reagents and potentiometric techniqueswere as described in refs. 9 and 10. Formation constantswere used in the COMPLOT program l1,l2 t o compute thedistribution of complexes present throughout the pHrange.RESULTS AND DISCUSSIONValues for logarithms of formation constants forprotonating the ligands and for forming iron(x1)-ligandcomplexes are given in Tables 1 and 2; pll0 values forfolate and malonate are omitted primarily becauseearlier researchers were unableLigand1 Gastrointestinal absorptionpromotionSide effectsw.r.t. FeSo41log PP*r101102103110210310Fe2+[FeOH]+Uncharged complexesTotal FeII complexedNegatively charged complexesConcn.of species at pH 7 (mM)TABLE 1Ligands studied as iron(I1) complexes in vizloAscorbate Citrate 0 Folate Q Fumarate+ + ( 7 )increased decreased10.35 & 0.05 5.62 8.26 4.3914-31 f 0.08 9-9612.907.09 & 0.01 4.4 2.78 f 0-044.997.19 f 0.037.90.1 3 0.04 0.46 0.390.49 0.14 1.70 1.463.38 1.01 d3-38 3.82 2.153.82 1.84 1.14 fto determine- them andGluconate adecreased3.86cSuccinatefdecreased5.19 f 0.019.13 f 0.011.42 f 0.292.920.812.990.160.200.04Data from ref.8.a 1 : 2 Iron(I1)-ligand.Refers to the complexes [(ligand),(rnetal ion),(proton),]. c Data not available. d 1 : 1 Iron (11)-ligand.f 1 : 2 and 1 : 3 Iron(n)-ligand.constants, p, and (ii) to calculate distribution curves ofiron(I1) between the range of complexes present in orderto seek correlations between the incidence of certaincomplexes and maximum intestinal absorption orminimal side effects, thus suggesting other absorption-promoting ligands which may have clinical advantages.Most of the ligands prescribed as ethical erythropoieticpreparations of iron in the United Kingdom6 wereexamined.Protonation pK values and formationconstants for their iron(x1) complexes were obtainedfrom the literature8 or, when in doubt, measured a t37 "C and I = 150m~-NaC10,.EXPERIMENTALThe following acids were used : L-ascorbic (B.D.H.,AnalaR), m.p. 191-193 "C (decomp.) [lit. 192 "C (decomp.)]L. Hallberg and L. Sdvell, Acta. Med. Scand., 1966, 23;A. Norrby, Scand. J . Haernat., 1971, 8, 104.Monthly Index of Medical Specialities, Haymarket Press,London, 1973.M. C. Berenbaum, K. J. Child, B. Davis, H. BI. Sharpe, andE. G. Tomich, Blood, 1980, 15, 540.so we assume that such species, even if they do exist,constitute insignificant amounts of the iron(@ ioncomplexed a t small intestinal pH values. Some of theformation constants in the Tables refer to conditionsother than 37 "C and I = 150m~-(Na)C10, and thisintroduces a marginal incompatibility into our models.However, the absorption-promotion observations andestimations of side effects are taken from reports bydifferent laboratories using different test systems,and so the p uncertainties are dwarfed by incompati-bilities in whole-body counting of radioactive iron inhuman beings and rat^,^.^ blood-sample counting ofradioactive iron in human being^,^ estimations of oral* ' Stability Constants of Metal-ion Complexes,' eds.L. G.Silldn and A. E. Martell, Chern. SOC. Spec. Publ., 1964, No. 17;1971, No. 26.!a D. R. Williams and P. A. Yeo, J.C.S. Dalton, 1972, 1988.lo A. D. Jones and D. R. Williams, J . Chem.Soc. ( A ) , 1971,l1 A. C. Baxter and D. R. Williams, J.C.S. Dalton, 1974,l2 D. D. Perrin and I. G. Sayce, Talanta, 1967, 14, 833.3138.11171974 1851toxicities in mice and rats, emetic activity in cats, [Fe2+]/[FeOH+] intersection pH values were all re-irritant effects on gastric mucosa in rabbits, and hema-tinic activities in rats.' The most important conclusion of this study is thatp Values for each of the ligands whose iron absorption- all three absorption-promoting systems [iron(rI) as-promotion effects had been investigated in vivo (and that corbate, fumarate, and succinate] have 1 : 1 neutralof [FeOH]+ (ref. 8)) were used in a COMPLOT l1 model complexes present in fairly high concentrations at pH 7computation of conditions in the intestine a t various (see Figure 2).Although these were not the majorsearched (see Table 1).TABLE 2Ligands studied as iron(I1) complexes in vitroGalact-Ligand -4s.partate a uronate Glutamate a JIalate a Malonate a Oxalate Salicylate Tartrate a1% PPYI101 0.46 11.42 & 0.04 9.41 6.1 1 5.34 2-59 13.0 4.37102 13.14 14.65 0.08 13-46: 8.55 8-19 3-92 18-81 7.39103 15-78110 4.34 9.7 & 0.6 3.52 2.68 c 3.06 6.55 2.24210 S.5 18.3 0.6 9.22 5-15 11.25 7-09plexes at pH 7 (mhi) 0.40 0.48 0.08 1.57 C 1.60 0.02 0.04Concn. of unchanged corn-a Data froni ref. 8. Refers to the complexes [(ligand),(metal ion),(proton),]. C Data not available.pH values (total Fe2+ and ligand concentrations =4.00 and t3.00mrYI, as used in most of the in vivo experi-ments).Examples of the plotter output are shownin Figure 1. Patterns relating absorption promotion,or side effects, to these concentrations were searchedfor amongst [Fe2+J, [FeOH+], molarities of unchargediron( 11)-1igand complexes, negatively charged iron(I1)-ligand complexes, and the total iron(1r) complexed.In addition, correlations involving pH values of the peakFIGURE 1 Complex concentration as a function of pH in theiron(i~)-succinate system: (1): Fe2+; (2), [FeOH]+; (3),[Fe(succinate)] ; (4), [Fe(suc~inate),]~--; ( 5 ) , Hsuccmate-;and (6), H,succinateconcentrations of the mono-, bis-, and tris-complexes,molecular weights of the most prevalent species, andspecies present at this pH, the concentrations of eachof the complexes are buffered (by the presence of theFIGURE 2 Concentrations of 1 : 1 neutral iron(I1) complexes insystems whose absorption-promotion characteristics have(-), and have not (- - -), been investigated in uivo:(l), ascorbate; (2), fumarate; (3), succinate; (4), aspartate;( 6 ) , galacturonate; (6), malate; and (7), oxalateother complexes and the ligand-proton system) andso passage of the 1 : 1 iron(I1)-ligand complex into theintestinal lining would merely require the bufferingcapacity of the intestinal fluid to replenish the concen-tration of the 1 : I complex at the expense of the 2 : 1complex.These computer-model studies suggest the followingfactors for improving oral-iron preparations.Iron(r1)complexes of other 2- carboxylic acid anions might bJ.C.S.Daltontested in animal experiments. Table 2 lists p valuesobtained from the literature for a range of such ligands,computer models suggesting that aspartate, galacturon-ate, and malate form the desired high concentration ofneutral 1 : 1 complex at pH 7 . (The [iron(n) oxalate]figure is also high but need not involve animal testsbecause of the toxicity of the parent acid.13) Lakatoset al. have suggested using polymers in the form ofliumic acids to increase metal ab~orpti0n.l~ Teratoet al. have promoted iron absorption using polymershaving a molecular weight of less than 10000.15 Pro-vided that the iron(r1)-polymer complex satisfies theuncharged complex at pH 7 criterion we envisage suchpolymer systems having additional advantages in thatpolymers tend to become adsorbed on to the intestinalwall (thus encouraging the first stage of their absorption),l3 I. L. Finar, ‘ Organic Chemistry,’ 3rd edn., Longmans,London, 1953, vol. 1.and, further, as compared to 1 : 1 iron(II)-ligand com-plexes in Tables 1 and 2 in which four of the metal-ionbonding positions are aquated (and so vulnerable tohydrolysis), iron( r1)-polymer complexes are expectedto be less aquated and consequently more resistanr: tohydrolysis a t pH 7. A naturally occurring polymerthat appears to satisfy these criteria is pectic acid(polygalacturonic acid, Af -N 3 000). It was encourag-ing to find that the monomeric unit, galacturonate,complexes with iron(I1) ions according to our neutralcomplex criterion. Clearly many more in vivo andiiz vitro studies are necessary to test the concepts dis-cussed in this paragraph.[3/2600 Receiucd, 28th Desenzbev, 1073;l4 B. Lskatos, J. Meisel, G. Mady, P. Winkler, and S. Sipos,15 I<. Terato, T. Fiyita, and Y. Yoshino, Digestive Diseases,Pvoc. Ipzternat. Peat, Congress, Helsinki, 1972, 371.1973, 18, 121
ISSN:1477-9226
DOI:10.1039/DT9740001849
出版商:RSC
年代:1974
数据来源: RSC