糖尿病肾病移植受者中环孢素代谢物浓度显著降低。

The concentration of cyclosporine metabolites is significantly lower in kidney transplant recipients with diabetes mellitus.

机构信息

Department of Biomedical and Pharmaceutical Sciences, Clinical Pharmacokinetics Research Laboratory, University of Rhode Island, Kingston, Rhode Island 02881, USA.

出版信息

Ther Drug Monit. 2012 Feb;34(1):38-45. doi: 10.1097/FTD.0b013e318241ac71.

DOI:10.1097/FTD.0b013e318241ac71

PMID:22210099

Abstract

BACKGROUND

Diabetes mellitus is prevalent among kidney transplant recipients. The activity of drug metabolizing enzymes or transporters may be altered by diabetes leading to changes in the concentration of parent drug or metabolites. This study was aimed to characterize the effect of diabetes on the concentration of cyclosporine (CsA) and metabolites.

METHODS

Concentration-time profiles of CsA and metabolites (AM1, AM9, AM4N, AM1c, AM19, and AM1c9) were characterized over a 12-hour dosing interval in 10 nondiabetic and 7 diabetic stable kidney transplant recipients. All patients were male, had nonfunctional CYP3A5*3 genotype, and were on combination therapy with ketoconazole.

RESULTS

The average daily dose (±SD) of CsA was 65 ± 21 and 68 ± 35 mg in nondiabetic and diabetic subjects, respectively (P = 0.550). Cyclosporine metabolites that involved amino acid 1 (AM1, AM19, AM1c) exhibited significantly lower dose-normalized values of area under the concentration-time curve in patients with diabetes. Moreover, during the postabsorption phase (≥3 hours after dose), metabolite-parent concentration ratios for all metabolites, except AM4N, was significantly lower in diabetic patients. The pharmacokinetic parameters of ketoconazole were similar between the 2 groups thus excluding inconsistent ketoconazole exposure as a source of altered CsA metabolism.

CONCLUSIONS

This study indicates that diabetes mellitus significantly affects the concentration of CsA metabolites. Because CsA is eliminated as metabolites via the biliary route, the decrease in the blood concentration of CsA metabolites during postabsorption phase would probably reflect lower hepatic cytochrome P450 3A4 enzyme activity. However, other mechanisms including altered expression of transporters may also play a role. Results of cyclosporine therapeutic drug monitoring in diabetic patients must be interpreted with caution when nonspecific assays are used.

摘要

背景

糖尿病在肾移植受者中较为常见。药物代谢酶或转运体的活性可能因糖尿病而改变，导致母体药物或代谢物的浓度发生变化。本研究旨在探讨糖尿病对环孢素（CsA）及其代谢物浓度的影响。

方法

在 10 名非糖尿病和 7 名糖尿病稳定型肾移植受者中，在 12 小时给药间隔内，对 CsA 及其代谢物（AM1、AM9、AM4N、AM1c、AM19 和 AM1c9）的浓度-时间曲线进行了特征描述。所有患者均为男性，具有非功能 CYP3A5*3 基因型，并接受酮康唑联合治疗。

结果

非糖尿病和糖尿病患者的 CsA 平均日剂量（±SD）分别为 65±21 和 68±35mg（P=0.550）。在糖尿病患者中，涉及氨基酸 1（AM1、AM19、AM1c）的环孢素代谢物的剂量标准化 AUC 值明显较低。此外，在吸收后阶段（给药后≥3 小时），除 AM4N 外，所有代谢物的母体-代谢物浓度比在糖尿病患者中均显著降低。两组患者的酮康唑药代动力学参数相似，因此可排除酮康唑暴露不一致是 CsA 代谢改变的原因。

结论

本研究表明，糖尿病显著影响 CsA 代谢物的浓度。由于 CsA 作为代谢物通过胆汁途径消除，吸收后阶段 CsA 代谢物的血药浓度降低可能反映了肝细胞色素 P450 3A4 酶活性降低。然而，其他机制，包括转运体表达的改变，也可能起作用。当使用非特异性检测方法时，必须谨慎解释糖尿病患者的环孢素治疗药物监测结果。