The acute porphyrias are a group of neuropsychiatric disorders in which a life-threatening crisis can be precipitated by a variety of drugs, including antidepressants. Because of the need to find an antidepressant that is safe for porphyria patients, we have studied the effects of lofepramine on porphyria in laboratory rats and porphyria patients. The rats did not exhibit a significant rise in hepatic δ-aminolaevulinic acid synthase activity (a marker of drug porphyrinogenicity) when given the drug compared with its solvent alone. Four porphyria patients exhibited no clinical evidence of disease activation after exposure to the drug. The biochemical activity of their disease was assessed by measurement of the 24-h urinary excretion of δ- aminolaevulinic acid and porphobilinogen (haem precursors formed prior to the metabolic block). No patient exhibited a sustained rise compared to pre-treatment levels, or between low dose and high dose lofepramine. We suggest that lofepramine is probably safe in acute porphyria, but should be used with caution.
Bloomer J.A., Savik K., Gross C.R. et al. (1993) Mortality in symptomatic acute intermittent porphyria. Gastroenterology18: 127A
2.
De Matteis F. (1975) The effect of drugs on delta-aminolaevulinate synthetase and other enzymes in the pathway of liver haem biosynthesis. In Parke D V (ed.), Enzyme induction. Plenum Press, London, New York , pp. 185-205
3.
Eales L. (1979) Porphyria and the dangerous life-threatening drugs . S Afr Med J56: 914-917
4.
Fitzsimons E.J., May A., Elder G.H., Jacobs A. (1986) Measurement of 5-aminolaevulinic acid synthase activity in whole and fractionated human bone marrow. Anal Biochem153: 9-17
5.
Goldberg A. (1959) Acute intermittent porphyria. A study of fifty casesQ J Med28: 183-209
6.
Gram T.E., Gillette J.P. (1971) Biotransformation of drugs. In Bacq Z M, Capek R, Puolatti R, Benson J (eds), Fundamentals of biochemical pharmacology. Pergamon Press, Oxford, p. 598
7.
Gunnarsson P.O., Andersson S-B., Ellman M., Olsson A. (1982) Metabolism of lofepramine by rat liver microsomes . Xenobiotica12: 83-91
8.
Herrick A.L., Thompson G.G., Graham A.M., McColl K E L, Medley I., Moore M.R. (1989) Effects of some antidepressant drugs on rat hepatic 5-aminolaevulinate synthase. Trans Biochem Soc16: 847-848
9.
Houston T. (1990) Haem biosynthesis in isolated human erythroblasts . PhD Thesis, University of Glasgow
10.
Krummel S.J., Wesner R.B. (1986) Exacerbation of acute intermittent porphyria by nortriptyline. Drug Intell Clin Pharm20: 487-488
11.
Mauzerall D., Granick S. (1956) The occurrence and determination of 5-aminolaevulinic acid and porphobilinogen in urine. J Biol Chem219: 435-446
12.
Maxwell J.D., Meyer U.A. (1978) Pharmacogenetics in the field of heme metabolism: drug sensitivity in hereditary hepatic porphyria. In de Matteis F, Aldridge W N (eds), Heme and hemoproteins. Springer Verlag, Berlin, pp. 239-254
13.
Moore M.R. (1983) Laboratory investigation of disturbances of porphyrin metabolism. Association of Clinical Pathologists Broadsheet10. British Medical Assocation
14.
Moore M.R., McColl K E L (1990) Porphyria drug lists. Hunter Press, Glasgow
15.
Moore M.R., McColl K E L, Rimington C., Goldberg A. (1987a) Disorders of porphyrin metabolism. Plenum Medical, New York and London
16.
Moore M.R., Thompson G.G., McColl K E L (1987b) The effects of some chemotherapeutic and immunosuppressive agents on 5-aminolaevulinate synthase. Trans Biochem Soc15: 679-680
17.
Oritz de Montellano R.P., Mico B.A., Yost G.S., Correia M.A. (1978) Suicidal inactivation of cytochrome P450; covalent binding of allyl-isopropylacetamide to the heme prosthetic group. In Seller N, Jung M J, Koch-Wesser J (eds), Enzyme activated irreversible inhibitors. Elsevier- North Holland Biomedical Press, Amsterdam, pp.337-352
18.
Parikh R.K., Moore M.R. (1978) Effect of certain anaesthetic agents on the activity of rat hepatic delta-aminolaevulinate synthase. Br J Anaesth50: 1099-1102
19.
Patience D.A. (1992) Acute intermittent porphyria and mental illness . M Phil Thesis, University of Edinburgh
20.
Peipkorn M.W., Hamernyik P., Labbe R.F. (1978) Modified erythrocyte uroporphyrin-1-synthetase assay and its clinical interpretation. Clin Chem24: 1751-1754
21.
Peters P.G., Sharma M.L., Hardwicke D., Piper W.N. (1980) Sulfonamide inhibition of rat hepatic uroporphyrinogen I synthase activity and biosynthesis of haem. Arch Biochem Biophys201: 88-94
22.
Rifkind A.B., Gillette P.N., Song C.S., Kappas A. (1973) Drug stimulation of delta-aminolaevulinic acid synthetase and cytochrome P450 in vivo in chick embryo liver. J Pharmacol Exp Ther185: 214-225
23.
Smith A.G., De Matteis F. (1980) Drugs and the hepatic porphyrias. In Goldberg A, Moore M R (eds), Clinics in haematology—the porphyrias. Saunders, London, Philadelphia , Toronto, pp. 339-425
24.
Stein J.A., Tschudy D.P. (1970) Acute intermittent porphyria—a clinical and biochemical study of 46 patients. Medicine Baltimore) 49:1-16
25.
Tephly T.R., Hasegawa E., Baron J. (1971) Effect of drugs on haem synthesis in the liver . Metabolism20: 200-214
26.
Tishler P.V., Woodward B., O'Connor J., Holbrook D.A., Seidman L.J., Hallet M., Knighton D.J. (1985) High prevalence of acute intermittent porphyria in a psychiatric patient population. Am J Psychiatr142: 1430-1436
27.
Vaz F.J., Salcedo M.S. (1991) Fluoxetine treatment of depressive symptoms in acute intermittent porphyria. J Clin Psychiatr52: 138
