Pharmaceutical analysis of the oral iron chelator deferiprone (DMHP, L1)
Cite this article as: Lange, R., Lameijer, W., Slijkhuis, C. et al. Pharm World Sci (1996) 18: 142. doi:10.1007/BF00717730 Abstract
The oral iron chelator deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one, DMHP, L1 or CP20) can be a useful drug in patients with transfusional hemosiderosis. From 1987 about 1000 patients in 16 countries have taken this drug on the base of clinical trials or compassionate use. Since this compound is only available as a raw substance, it is important to ascertain its purity before bringing the drug into a pharmaceutical formulation. Because deferiprone is administered chronically and in high doses, intake of potential toxic impurities can be substantial.
In this article a proposal for the quality control of deferiprone is presented in the form of a pharmaceutical monograph. This includes the analytical methods required for identification, purity checking and assay. Furthermore the way we synthesized the drug to get hold of it in a pure form is described. This synthesis is also used in manufacturing the drug commercially. The monograph can be used as a guideline for standardization of the quality of deferiprone to be used for further study and treatment.
Keywords CP20 deteriprone 1,2-dimethyl-3-hydroxypyrid-4-one DMHP Iron overload L1 Oral iron chelator Pharmaceutical analysis Quality control Standardization Synthesis Transfusional hemosiderosis References
Hoffbrand AV, Wonke B. Results of long-term subcutaneous desferrioxamine therapy. Baillière's Clin Haemat 1989; 2: 345–62.
Brittenham GM, Griffith PM, Nienhuis AW, McLaren CE, Young NS, Tucker EE et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994; 331: 567–73.
Olivieri NF, Nathan DF, MacMillan JH, Wayne AS, Liu PP, McGee A et al. Survival in medically treated patients with homozygous β-thalassemia. N Engl J Med 1994; 331: 574–8.
Olivieri NF, Buncic JR, Chew E, Gallant T, Harrison RV, Keenan N et al. Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N Engl J Med 1986; 314: 869–73.
DeVergiliis S, Congia M, Frau F, Argiolu F, Diana G, Cucca F et al. Deferoxamine-induced growth retardation in patients with thalassemia major. J Pediatr 1988; 113: 661–9.
Porter J. Oral iron chelators: Prospects for future development. Eur J Haematol 1989; 43: 271–85.
Kontoghiorghes GJ, Sheppard L, Chambers S. New synthetic approach and iron chelation studies of 1-alkyl-2-methyl-3-hydroxypyrid-4-ones. Arzneim-Forsch/Drug Res 1987; 37: 1099–1102.
Kline MA, Orvig C. Complexation of iron with the orally active decorporation drug L1 (3-hydroxy-1,2-dimethylpyrid-4-inone). Clin Chem 1992; 38: 562–5.
Kontoghiorghes GJ, Hoffbrand AV. Prospects for effective and oral chelation in transfusional iron overload. Recent advances in Haematology 1988; 5: 75–98.
Kontoghiorghes GJ. Orally active alpha-ketohydroxypyridine iron chelators: effects on iron and other metal mobilizations. Acta Hematol 1987; 78: 212–6.
Kontoghiorghes GJ, Aldouri MA, Sheppard L, Hoffbrand AV. 1,2-Dimethyl-3-hydroxypyrid-4-one, an orally active chelator for treatment of iron overload. Lancet 1987; i: 1294–5.
Kontoghiorghes GJ, Aldouri MA, Hoffbrand AV, Barr J, Wonke B, Kourouklaris T, Sheppard L. Effective chelation in β thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one. Br Med J 1987; 295: 1509–12.
Kontoghiorghes GJ, Nasseri-Sina P, Goddard JG, Barr JM, Nortey P, Sheppard LN. Safety of oral iron chelator L1. Lancet 1989; ii: 457–8.
Kontoghiorghes GJ, Bartlett AN, Hoffbrand AV, Goddard JG, Sheppard L, Barr J, Nortey P. Long-term trial with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). I. Iron chelation and metabolic studies. Br J Haematol 1990; 76: 295–300.
Bartlett AN, Hoffbrand AV, Kontoghiorghes GJ. Long-term trial with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). II. Clinical observations. Br J Haematol 1990; 76: 301–4.
Goudsmit R. Langdurige onttrekking van ijzer met behulp van oraal toegediend 1,2-dimethyl-3-hydroxypyrid-4-one (L1) bij patiënten met transfusiehaemosiderose. Ned J Geneesk 1991; 135: 2133–6.
Agarwal MB, Gupte SS, Viswanathan C et al. Long-term assessment of efficacy and safety of L1, an oral iron chelator, in transfusion dependent thalassaemia: Indian trial. Br J Haemat 1992; 82: 460–66.
Al-Refaie FN, Wonke B, Hoffbrand AV, Wickens DG, Nortey P, Kontoghiorghes GJ. Efficacy and possible adverse effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in thalassemia major. Blood 1992; 80: 593–9.
Kontoghiorghes GJ. Update of worldwide iron chelation therapy with L1 (deferiprone). Abstracts 6th International Conference on Oral Chelation (ICOC), Nijmegen, 1995.
Al-Refaie FN, Herschko C, Hoffbrand AV, Kosaryan M, Oliveiri NF, Tondury P et al. Results of long-term deferiprone (L1) therapy: a report by the International Study Group on Oral Iron Chelators. Br J Haemat 1995; 91: 224–9.
Olivieri NF, Koren G, Hermann C, Bentur Y, Chung D, Klein J et al. Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients. Lancet 1990; 336: 1275–79.
Olivieri NF, Brittenham GM, Matsui D, Berkovitch M, Blendis LM, Cameron RG et al. Iron-chelation therapy with oral deferi-prone in patients with thalassemia major. N Engl J Med 1995; 332: 918–22.
Kontoghiorghes GJ, Goddard JG, Bartlett AN, Sheppard L. Pharmacokinetic studies in humans with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one. Clin Pharmacol Ther 1990; 48: 255–61.
Matsui D, Klein J, Hermann C, Grunau V, McClelland R, Chung D, St-Louis P, Olivieri N, Koren G. Relationship between the pharmacokinetics of the new oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one in patients with thalassemia. Clin Pharmacol Ther 1991; 50: 294–8.
Peratoner A, Tamburello A. Gazz Chim Ital 1906; 36: 50–57.
Kontoghiorghes GJ, Sheppard L. Simple synthesis of the potent iron chelators 1-alkyl-3-hydroxy-2-methylpyrid-4-one. Inorganica Chimica Acta 1987; 136: L11–12.
The European Pharmacopoeia, second edition, Maisonneuve.
Brittenham GM. Development of iron-chelating agents for clinical use. Blood 1992; 80: 569–74.
Politis C, Vrettou H, Fragatou S, Hatzilaou J, Richardson C, Cuindo S. Reactions to subcutaneous application of iron chelation therapy with desferrioxamine. An urgent need for oral chelators. Abstracts 4th International Conference on Oral Chelation (ICOC), Cyprus, 1993.
Kontoghiorghes GJ, Sheppard L, Barr J. Synthetic methods and in vitro iron binding studies of the novel 1-alkyl-2-ethyl-3-hydroxypyrid-4-one iron chelators. Inorg Chim Acta 1988; 152: 195–99.
Nelson WO, Karpishin TB, Rettig SJ, Orvig C. Physical and structural studies of N-substituted-3-hydroxy-2-methyl-4(1H)-pyridinones. Can J Chem 1988; 66: 123–31.
Epemolu RO, Singh R, Hider RC, Damani LA. Chromatography of 3-hydroxy-pyridin-4-ones; novel orally active iron chelators. J Chromatogr 1990; 519: 171–178.
Guide for the technical content of monographys, Pharmeuropa special edition 1993.
Gilad GM, Gilad VH. Cytotoxic effects of monodansylcadaverine and methylamine in primary cultures of rat cerebellar neurons. Int J Devl Neuroscience 1986; 4: 401–5.
LeBlanc, DT, Akers, HA. Maltol and ethyl maltol: from the larch tree to successful food addidive. Food Technology 1989; 78–84.
Bjeldanes LF, Chew H. Mutagenicity of 1,2-dicarbonyl compounds: maltol, kojic acid, diacetyl and related substances. Mutation Res 1979; 67: 367–71.
Shibarmoto T, Nishimura O, Mihara S. Mutagenicity of products obtained from a maltol-ammonia browning model system. J Agric Food Chem 1981; 29: 643–46.
Hayashi M, Kishi M, Sofuni T, Ishidate M. Micronucleus tests in mice on 39 food additives and eight miscellaneous chemicals. Fd Chem Toxic 1988; 26: 487–500.
Goddard JG, Kontoghiorghes GJ. Development of an HPLC method for measuring orally administered 1-substituted 2-alkyl-3-hydroxypyrid-4-one iron chelators in biological fluids. Clin Chem 1990; 36: 5–8.
Klein I, Damani LA, Chung D, Epemoulu O, Olivieri N, Koren C. A high-performance liquid chromatographic method for the measurement of the iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one in human plasma. Ther Drug Monit 1991; 13: 51–54.
Joint FAO/WHO expert committee on food additives. Geneva: WHO. Technical report series 669, 1981.
© Kluwer Academic Publishers 1996