Moore L W, Alloway R R, Acchiardo S R, Vera S R, Shokouh-Amiri M, Gaber A O
Department of Surgery, Division of Transplantation, University of Tennessee-Memphis 38163, USA.
Transplantation. 1996 Feb 27;61(4):537-41. doi: 10.1097/00007890-199602270-00004.
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.
酮康唑与负责环孢素降解的单加氧酶结合，会降低环孢素的代谢。这种细胞色素P450同工酶以及其他类似的单加氧酶参与胆固醇重要代谢途径的合成与降解调节。酮康唑与这些途径中的单加氧酶结合会产生抑制作用，导致骨化三醇、胆汁酸和类固醇激素的代谢减少，进而可能增强移植受者脂质代谢、骨代谢和体重状况的改变。将一组服用酮康唑的肾移植受者（n = 25）与一组匹配的未接受酮康唑治疗的队列进行比较，观察移植后前六个月的代谢变化。酮康唑组在术后1个月时的低密度脂蛋白胆固醇水平（109±8 mg/dl）低于未服用酮康唑组（140±8 mg/dl），但这种差异在术后6个月时未持续存在。酮康唑组发生了更多的骨质流失，这通过骨密度的显著变化以及骨胶原交联物脱氧吡啶啉在尿液中的大量出现得以证明（酮康唑组和未服用酮康唑组在术后6个月时分别为29±4 nmol dpd/mmol肌酐和18±4，P<0.05）。酮康唑组和未服用酮康唑组在术后6个月时的体重增加变化不同（分别为6.4±1.4 kg和5.0±1.3 kg），且酮康唑组随时间的体重增加速率加快（术后1个月时为0.02 kg/天，术后6个月时为0.05 kg/天，P<0.007）。酮康唑抑制环孢素的效果虽有价值，但对其他代谢途径的抑制作用也应进行评估。
