Andrews, C. M.; (2001) Studies on the haemotoxicity of busulphan and chloramphenicol in the b6c3f1 mouse. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Aplastic anaemia (AA) is a potentially fatal failure of haemopoiesis of unknown aetiology. In some cases, AA has been linked to drug administration, for example, chloramphenicol (CAP), phenylbutazone and gold salts. Recently, several drugs have been withdrawn following deaths from AA. There is at present no preclinical test, or animal model, predictive of drug-induced AA in man. The objective of the present work was first, to investigate the haemotoxicity of busulphan (BU) and CAP (as succinate, CAPS) in the B6C3F1 mouse, and second, to evaluate the toxicity of CAPS in BU-pretreated animals using standard haematological techniques. The maximum tolerated single dose (MTD) of BU was 45 mg/kg; myelosuppression was maximal at 2 days (d) with recovery after 7 d. Macrocytic anaemia, thrombocytopenia and leucopenia, persisted at 14 d post dosing, and after four fortnightly BU doses of 40 mg/kg, at 2 and 6 weeks post dosing. CAPS given in the drinking water at 4.0 mg/mL caused reversible haemoconcentration with reticulocytopenia, but not myelosuppression. BU was given at 40 mg/kg on d 1, 16, 30 and 43, followed by CAPS in the drinking water at 4.0 mg/mL from d 85 to 497. BU treatment alone resulted in deaths from aplasia up to d 168, thereafter deaths were due to lymphoma. Surviving BU-treated animals showed persistent thrombocytopenia and reductions in IgG+ lymphocytes, but no reticulocytopenia. No cumulative haemotoxic effect was seen in mice pretreated with BU and then given CAPS. CAP kinetics were studied after administration in drinking water, by gavage and intravenous (iv) dosing. CAPS and CAP were quickly metabolised and cleared, and only very low concentrations reached the bone marrow. Gavage dosing at 3500 mg/kg/d for 5 d induced reversible myelosuppression, with recovery at 5-10 d after dosing. In a second long-term experiment, BU was administered as before, but CAPS was gavaged at 3000 mg/kg/d, in 5-day pulses, in 21 d cycles. Deaths due to BU-induced aplasia and lymphoma were seen as before; no increased aplasia resulted from the administration of BU and CAPS. It is concluded that administration of BU to B6C3F1 mice induced aplasia in a proportion of animals. Giving high doses of CAPS by gavage caused reversible myelosuppression. However, administration of CAPS, following BU pretreatment, induced no increased haemotoxicity.

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