Cyclophosphamide metabolism in children with Fanconi's anaemia

Although patients with Fanconi's anaemia (FA) exhibit a heightened sensitiv ity to DNA cross-linking agents, modified doses of CY continue to be used i n their conditioning prior to BMT. We measured the pharmacokinetics and met abolism of CY in six children with FA using an established high performance thin layer chromatography technique. CY doses ranged between 5 and 20 mg/k g (median 10 mg/kg), The median CY clearance was 0.6 1/h/m(2) (range 0.4-1. 1 1/h/m(2)), t(1/2) was 8.1 h (range 6.7-9.5 h) and volume of distribution was 0.19 1/kg (range 0.16-0.34 1/kg), respectively. These results contrast with those previously reported from a comparable group of non-FA children i n whom the median CY clearance was 3.2 1/h/m(2) (range 2-5 1/h/m(2)) (P = 0 .035), t(1/2) was 2.4 h (range 2-3.8 h) (P = 0.035) and volume of distribut ion 0.5 1/kg (range 0.26-0.95 1/kg) (NS), Unlike the control group in whom the presence of inactive metabolites of CY was common, metabolites could no t be found in any FA patient. The enhanced sensitivity of children with FA to CY may in part result from altered drug metabolism.