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Haemotoxicity of chloramphenicol succinate in the CD-1 mouse and Wistar Hanover rat

D Yallop

Centre for Toxicology, Department of Pharmacology, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK

C M Andrews

R Fagg

M York

T C Williams

GlaxoWellcome Research and Development, Park Road, Ware, Herts SG12 0DP, UK

1. 1 Chloramphenicol has been widely used in the treatment of serious infections including typhoid fever and meningitis. However, the drug is haemotoxic in man inducing firstly, a reversible, dose-dependent anaemia which develops during treatment, secondly, an often fatal aplastic anaemia with pancytopenia and acellular marrow, and thirdly, leukaemia.
   
2. 2 We investigated the haemotoxicity of chloramphenicol succinate (CAPS) in female CD-1 mice in repeat dose studies, to compare the response with the reversible anaemia reported in man. Studies in male Wistar Hanover rats were also carried out.
   
3. 3 CAPS was gavaged daily to mice at dose levels from 800–2000 mg/kg for seven days. Values were significantly reduced for reticulocytes at 1700 and 2000 mg/ kg, and for erythrocytes (RBC), haematocrit (HCT), and haemoglobin (Hb) at 2000 mg/kg. Platelet and white blood cell (WBC) counts were unaffected.
   
4. 4 Mice were dosed with CAPS at 1400 mg/kg for 10 days and sampled at 1, 4 and 15 days after the last dose. At day 1 post dosing, RBC, HCT and Hb values were significantly reduced, but returned to normal (or above normal) by day 4 or 15.
   
5. 5 CAPS from 2000–4000 mg/kg was gavaged to rats daily for 19 days. Hb values were significantly lower at 3600 and 4000 mg/kg; reticulocytes were not reduced. WBC and platelet counts, in general, were unaffected.
   
6. 6 Levels of apoptosis in marrow mononuclear cells were increased in CAPS-treated mice, but not in CAPS-treated rats. Serum biochemistry parameters, in general, showed few changes of toxicological significance.
   
7. 7 We conclude that the administration of CAPS to CD-1 mice induced haematological changes showing close parallels with the chloramphenicol-induced reversible anaemia seen in man.
   

Key Words: chloramphenicol succinate • haemotoxicity • mouse • rat • aplastic anaemia

Human & Experimental Toxicology, Vol. 18, No. 9, 566-576 (1999)
DOI: 10.1191/096032799678845098


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