CLINICAL OBSERVATIONS OF METABOLIC CHANGES OCCURRING IN RENAL-TRANSPLANT RECIPIENTS RECEIVING KETOCONAZOLE

Metabolism of cyclosporine is reduced by ketoconazole binding to the m onooxygenase responsible for cyclosporine degradation, This isozyme of cytochrome P450, along with other similar monooxygenases, is involved in the regulation of the synthesis and degradation of important metab olic pathways of cholesterol, Monooxygenases throughout these pathways are inhibited by ketoconazole binding causing a decreased metabolism of calcitriol, bile acids, and steroid hormones, and can thereby poten tiate altered lipid metabolism, bone metabolism and weight status of t ransplant recipients, A group of renal transplant recipients taking ke toconazole (n=25) was compared with a matched cohort not receiving ket oconazole for metabolic changes during the first six months posttransp lantation, Lower LDL cholesterol levels were seen in the ketoconazole group (109+/-8 mg/dl) than the no ketoconazole group (140+/-8 mg/dl) a t one month but this difference was not sustained at six months, More bone loss occurred in the ketoconazole group as demonstrated by signif icant changes in bone density as well as a greater urinary appearance of bone collagen crosslink, deoxypyridinoline (29+/-4 nmol dpd/mmol cr eatinine and 18+/-4 at six months for the ketoconazole group versus th e no ketoconazole group, respectively, P<0.05), Weight gain changes we re different between the ketoconazole group and no ketoconazole group (6.4+/-1.4 kg versus 5.0+/-1.3 kg) at six months and an increased rate of weight gain over time in the ketoconazole group (0.02 kg/day at on e month versus 0.05 kg/day at six months, P<0.007), Effectiveness of k etoconazole inhibition of cyclosporine is valuable, but inhibition of other metabolic pathways should be evaluated as well.