Clinical observations of metabolic changes occurring in renal transplant recipients receiving ketoconazole.
Metabolism of cyclosporine is reduced by ketoconazole binding to the monooxygenase 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 metabolic 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 potentiate altered lipid metabolism, bone metabolism, and weight status of transplant recipients. A group of renal transplant recipients taking ketoconazole (n=25) was compared with a matched cohort not receiving ketoconazole for metabolic changes during the first six months posttransplantation. Lower LDL cholesterol levels were seen in the ketoconazole group (109 +/- 8 mg/dl) than the no ketoconazole group (140 +/- 8 mg/dl) at one month but this difference was not sustained at six months. More bone loss occurred in the ketoconazole group as demonstrated by significant changes in bone density as well as a greater urinary appearance of bone collagen crosslink, deoxy-pyridinoline (29 +/- 4 nmol dpd/mmol creatinine and 18 +/- 4 at six months for the ketoconazole group versus the no ketoconazole group, respectively, P<0.05). Weight gain changes were 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 one month versus 0.05 kg/day at six months, P<0.007). Effectiveness of ketoconazole inhibition of cyclosporine is valuable, but inhibition of other metabolic pathways should be evaluated as well.
Moore
L W
LW
Department of Surgery, Division of Transplantation, University of Tennessee-Memphis 38163, USA.
Alloway
R R
RR
Acchiardo
S R
SR
Vera
S R
SR
Shokouh-Amiri
M
M
Gaber
A O
AO
D000293:Adolescent; D000328:Adult; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002648:Child; D002784:Cholesterol / Q000097:blood; D016572:Cyclosporine / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007654:Ketoconazole / Q000378:metabolism / Q000627:therapeutic use*; D016030:Kidney Transplantation; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D008055:Lipids; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D007654:Ketoconazole; D011241:Prednisone