替米沙坦、缬沙坦和坎地沙坦对日本肾移植受者吗替麦考酚酯药代动力学的影响。
Effect of telmisartan, valsartan and candesartan on mycophenolate mofetil pharmacokinetics in Japanese renal transplant recipients.
机构信息
Department of Pharmacy, Akita University Hospital, Akita, Japan.
出版信息
J Clin Pharm Ther. 2009 Dec;34(6):683-92. doi: 10.1111/j.1365-2710.2009.01053.x.
OBJECTIVE
The aim of this study was to elucidate the effect of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activating angiotensin receptor blocker (ARB) telmisartan and the non-PPAR-gamma activating ARB valsartan and candesartan on mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients.
METHODS
Recipients (n = 10 each group) were randomly given either 40 mg of telmisartan, 80 mg of valsartan or 8 mg of candesartan cilexetil for at least 6 months, and no ARB. Blood was sampled a year after transplantation.
RESULTS
Dose-adjusted maximum and trough plasma concentration of MPA co-administered with telmisartan were the lowest in all groups. The mean dose-adjusted area under the concentration curve from 0 to 12 h (AUC(0-12)) and AUC(0-6) of MPA co-administered with telmisartan were significantly lower than that without ARB (98 vs. 138 ng x h/mL/mg, P = 0.0353 and 63 vs. 96 ng x h/mL/mg, P = 0.0305). Coadministration of valsartan and candesartan did not alter MPA pharmacokinetics. The AUC ratio of MPA glucuronide (MPAG)/MPA co-administered with telmisartan was higher than that without ARBs, but not significantly (14.2 vs. 9.1). The mean maximum and minimum plasma concentrations of telmisartan (40 mg) after oral administration were 84 and 15 ng/mL, respectively, and that of valsartan (80 mg) 2220 and 441 ng/mL, respectively. Plasma concentrations of candesartan in most transplant patients were not observed 19 h after oral administration of candesartan cilexeil (8 mg).
CONCLUSIONS
The degree of drug interaction between MPA and telmisartan was significantly greater than that between MPA and valsartan or candesartan. Uridine diphosphate-glucuronosyltransferase (UGT) 1A9 has been identified as a PPAR-gamma target gene. UGT induction by telmisartan might stimulate MPA glucuronidation. A combination of telmisartan and mycophenolate mofetil might require periodic monitoring of MPA.
目的
本研究旨在阐明过氧化物酶体增殖物激活受体-γ（PPAR-γ）激动型血管紧张素受体阻断剂（ARB）替米沙坦和非 PPAR-γ激动型 ARB 缬沙坦和坎地沙坦对肾移植受者麦考酚酸（MPA）药代动力学的影响。
方法
将患者（每组 10 例）随机给予替米沙坦 40mg、缬沙坦 80mg 或坎地沙坦西酯 8mg，至少 6 个月，不使用 ARB。移植后 1 年采集血样。
结果
与替米沙坦合用的 MPA 最大和最低血浆浓度经剂量调整后在所有组中最低。与未用 ARB 相比，替米沙坦合用的 MPA 0 至 12 小时（AUC（0-12））和 AUC（0-6）的平均剂量调整面积显著降低（98 与 138ng×h/mL/mg，P=0.0353 和 63 与 96ng×h/mL/mg，P=0.0305）。缬沙坦和坎地沙坦合用并未改变 MPA 药代动力学。与未用 ARB 相比，替米沙坦合用的 MPA 葡萄糖醛酸（MPAG）/MPA 的 AUC 比值较高，但无统计学意义（14.2 与 9.1）。替米沙坦（40mg）口服后的平均最大和最小血浆浓度分别为 84 和 15ng/mL，缬沙坦（80mg）分别为 2220 和 441ng/mL。坎地沙坦西酯（8mg）口服后 19 小时，大多数移植患者的血浆坎地沙坦浓度未被观察到。
结论
MPA 与替米沙坦的药物相互作用程度明显大于 MPA 与缬沙坦或坎地沙坦。尿苷二磷酸-葡萄糖醛酸基转移酶（UGT）1A9 已被确定为 PPAR-γ 靶基因。替米沙坦诱导 UGT 可能刺激 MPA 葡萄糖醛酸化。替米沙坦和吗替麦考酚酯的联合使用可能需要定期监测 MPA。
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