An investigation of the role of metabolism in dapsone‐induced methaemoglobinaemia using a two compartment in vitro test system.

British Journal of Clinical Pharmacology - Tập 30 Số 6 - Trang 829-838 - 1990
Malcolm D. Tingle1, Michael D. Coleman1, BK Park1
1Department of Pharmacology & Therapeutics, University of Liverpool.

Tóm tắt

1. We have utilized a two compartment system in which two teflon chambers are separated by a semi‐permeable membrane in order to investigate the role of metabolism in dapsone‐induced methaemoglobinaemia. Compartment A contained a drug metabolizing system (microsomes prepared from human liver +/‐ NADPH), whilst compartment B contained target cells (human red cells). 2. Incubation of dapsone (1‐ 100 microM) with human liver microsomes (2 mg protein) and NADPH (1 mM) in compartment A (final volume 500 microliters) led to a concentration‐ dependent increase in the methaemoglobinaemia (15.4‐18.9% at 100 microM) compared with control (2.3 +/‐ 0.4%) detected in the red cells within compartment B. In the absence of NADPH dapsone had no effect. 3. Of the putative dapsone metabolites investigated, only dapsone‐ hydroxylamine caused methaemoglobin formation in the absence of NADPH (40.6 +/‐ 6.3% with 100 microM). However, methaemoglobin was also detected when monoacetyl‐dapsone, 4‐amino‐4′‐nitro‐diphenylsulphone and 4‐aminoacetyl‐4′‐nitro‐diphenylsulphone were incubated with human liver microsomes in the presence of NADPH. 4 Dapsone‐dependent methaemoglobin formation was inhibited by addition of ketoconazole (1‐1000 microM) to compartment A, with IC50 values of 285 and 806 microM for the two liver microsomal samples studied. In contrast, methaemoglobin formation was not inhibited by cimetidine or a number of drugs pharmacologically‐ related to dapsone. The presence of glutathione or ascorbate (500 microM) did not alter the level of methaemoglobin observed.

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Tài liệu tham khảo

10.1016/0165-1161(75)90046-1

Barnes J., 1951, Liver damage during treatment with DDS., Lepr. Rev., 12, 54

Bruce‐Chwatt L. J., 1982, Essential malariology.

10.1111/j.1365-2125.1989.tb03517.x

10.1111/j.2042-7158.1990.tb06562.x

10.1016/0006-2952(90)90164-G

DeGowin R. L., 1966, The haemolytic effects of diaphenylsulphone (DDS) in normal subjects and in those with glucose 6‐phosphate dehydrogenase deficiency., Bull. World Health Org., 35, 165

Glader B. F., 1973, Haemolysis by diphenylsulfones: Comparative effects of DDS and hydroxylamine‐DDS., J. lab. clin. Med., 81, 267

10.1002/cpt1971122part1225

Grindulis K. A., 1984, Rheumatoid arthritis, the effects of treatment with dapsone on haemoglobin., J. Rheumatol., 11, 776

Grossman S. J., 1988, Role of dapsone hydroxylamine in dapsone‐induced haemolytic anemia., J. Pharmac. exp. Ther., 244, 118

Harrison J. H., 1986, Role of aniline metabolites in aniline‐induced haemolytic anemia., J. Pharmac. exp. Ther., 238, 1045

Israili Z. H., 1973, Studies of the metabolism of dapsone in man and experimental animals: Formulation of N‐hydroxy metabolites., J. Pharmac. exp. Ther., 187, 138

10.1016/0006-2952(85)90408-3

10.1016/0006-2952(72)90288-2

10.1016/S0190-9622(79)80088-2

10.3109/00498258909042286

Mitchell M. C., 1981, Cimetidine protects against acetaminophen hepatotoxicity in rats., Gastroenterol., 81, 1052, 10.1016/S0016-5085(81)80011-X

10.1016/0006-2952(80)90448-7

Omura T., 1964, The carbon monoxide binding pigment of liver microsomes., J. biol. Chem., 239, 2370, 10.1016/S0021-9258(20)82244-3

10.1111/j.1365-2125.1987.tb03074.x

10.1016/0006-2952(83)90584-1

10.1111/j.1365-2125.1988.tb05298.x

10.1111/j.1365-2125.1990.tb03793.x

Salem Z., 1981, The nitroreduction of chloramphenicol by human liver tissue., J. lab. clin. Med., 97, 881

Sheets J. J., 1984, Ketoconazole: A potent inhibitor of cytochrome P‐450‐dependent drug metabolism in rat liver., Drug Metab. Dispos., 12, 603

Smith W. C. S., 1988, Are hypersensitivity reactions to dapsone becoming more frequent?, Lepr. Rev., 59, 53

Spielberg S. P., 1984, In vitro assessment of pharmacogenetic susceptibility to toxic drug metabolite in humans., Fed. Proc., 43, 2308

10.1007/BF00501863

Uetrecht J., 1988, Metabolism of dapsone to a hydroxylamine by human neutrophils and mononuclear cells., J. Pharmac. exp. Ther., 245, 274

Wright J. T., 1984, Cimetidine and dapsone acetylation., Drugs Metab. Disp., 12, 782

10.2165/00003088-198611040-00003

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British Journal of Clinical Pharmacology

Tập 30 Số 6

829-838

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