Böhmer Gabriele M, Drollmann Anton, Gleiter Christoph H, Nave Rüdiger
Department of Clinical Pharmacology, University Hospital of Tübingen, Tübingen, Germany.
Clin Pharmacokinet. 2008;47(5):343-9. doi: 10.2165/00003088-200847050-00005.
Cytochrome P450 (CYP) 3A4 isoenzyme has been identified in vitro as the key enzyme to metabolize desisobutyryl-ciclesonide (des-CIC), the pharmacologically active metabolite of the inhaled corticosteroid ciclesonide. This pharmacokinetic drug-drug interaction study was conducted to confirm this major metabolic pathway in vivo by using the strong CYP3A4 inhibitor ketoconazole, and to assess the effect of ketoconazole on the pharmacokinetics of ciclesonide and des-CIC.
Fourteen healthy adults participated in this open-label, nonrandomized, fixed sequence, two-period, repeated-dose pharmacokinetic study. During the first 7-day treatment period, the subjects orally inhaled ciclesonide 320 microg once daily. During the second 7-day treatment period, the subjects continued with the same dose of orally inhaled ciclesonide and concomitantly received oral ketoconazole 400 mg once daily. Pharmacokinetic profiles for ciclesonide and des-CIC were obtained on day 7 of each study period.
For the parent compound, ciclesonide, no changes in the pharmacokinetic parameter estimates--the area under the serum concentration-time curve during the dosage interval (AUC(tau)), maximum serum concentration (C(max)) and time to reach the C(max)--were observed. In contrast, the AUC(tau) and C(max) of des-CIC increased approximately 3.5-fold and 2-fold under the influence of the CYP3A4 inhibitor ketoconazole.
The CYP3A4 pathway is the major pathway for biotransformation of the active metabolite of ciclesonide in humans. While elimination of des-CIC was reduced by strong CYP3A4 inhibitor coadministration in vivo, activation of the parent compound ciclesonide to des-CIC was not affected. Dose adjustment is not necessary when ciclesonide needs to be coadministered with ketoconazole, because the potency of an inhaled corticosteroid is mediated by topical concentrations in the lung and because ciclesonide has a very low potential to produce systemic adverse effects.
细胞色素P450（CYP）3A4同工酶在体外已被确定为代谢去异丁酰基环索奈德（des - CIC）的关键酶，des - CIC是吸入性糖皮质激素环索奈德的药理活性代谢产物。本药代动力学药物相互作用研究通过使用强效CYP3A4抑制剂酮康唑来在体内证实这一主要代谢途径，并评估酮康唑对环索奈德和des - CIC药代动力学的影响。
14名健康成年人参与了这项开放标签、非随机、固定顺序、两期、重复给药的药代动力学研究。在第一个7天治疗期内，受试者每日口服吸入一次320微克环索奈德。在第二个7天治疗期内，受试者继续使用相同剂量的口服吸入环索奈德，并同时每日口服一次400毫克酮康唑。在每个研究期的第7天获取环索奈德和des - CIC的药代动力学曲线。
对于母体化合物环索奈德，未观察到药代动力学参数估计值的变化——给药间隔期间血清浓度 - 时间曲线下面积（AUC(tau)）、最大血清浓度（C(max)）以及达到C(max)的时间。相比之下，在CYP3A4抑制剂酮康唑的影响下，des - CIC的AUC(tau)和C(max)分别增加了约3.5倍和2倍。
CYP3A4途径是环索奈德活性代谢产物在人体内生物转化的主要途径。虽然在体内联合使用强效CYP3A4抑制剂会减少des - CIC的消除，但母体化合物环索奈德向des - CIC的活化不受影响。当环索奈德需要与酮康唑联合使用时无需调整剂量，因为吸入性糖皮质激素的效力由肺部局部浓度介导，且环索奈德产生全身不良反应的可能性非常低。
