Unexpected effect of verapamil on oral bioavailability of the β‐blocker talinolol in humans
Unexpected effect of verapamil on oral bioavailability of the β‐blocker talinolol in humans
复制标题
维拉帕米对人体 β 阻滞剂他林洛尔口服生物利用度的意外影响
DOI：
10.1016/s0009-9236(99)70107-4
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发表时间：
1999
影响因子：
6.7
通讯作者：
W. Kirch
中科院分区：
文献类型：
--
作者：
U. Schwarz;T. Gramatté;J. Krappweis;A. Berndt;R. Oertel;O. Richter;W. Kirch
目的定量观察口服维拉帕米（钙通道阻滞剂和P糖蛋白抑制剂）对P糖蛋白底物β1肾上腺素能受体拮抗剂他立洛尔口服药代动力学的影响。在一项随机、交叉安慰剂对照研究中，研究了9名健康志愿者在同时服用单剂量r -维拉帕米（120 mg）或安慰剂后，口服他他洛尔（50 mg）的药代动力学。用高效液相色谱法测定他他洛尔、维拉帕米及其主要代谢物诺维拉帕米在血清中的浓度。同时用高效液相色谱法测定尿中他他洛尔的浓度。标准药代动力学参数采用非室区程序计算。结果与安慰剂相比，r‐维拉帕米治疗后0 ~ 24 h他利洛尔浓度-时间曲线下面积（721±231 ng·h·mL - 1）显著降低（945±188 ng·h·mL - 1）；与安慰剂相比，服用r -维拉帕米后他他洛尔的最高血清浓度明显提前达到（P< 0.05）。r -维拉帕米联合给药不影响肾脏清除率或他他洛尔的半衰期。血清药代动力学与尿中他林洛尔浓度的结果是平行的。结论：这是第一个显示P糖蛋白底物（他他洛尔）在人体内口服生物利用度降低的研究，因为同时给药维拉帕米。这种影响被认为是由他他洛尔的肠道吸收改变引起的，因为他他洛尔的肾脏清除不受r -维拉帕米的影响。r -维拉帕米的这种意想不到的效果很可能是由于肠道P糖蛋白和肠道代谢之间的相互作用而产生的剂量依赖性。临床药理学与治疗学（1999）65,283-290；doi:
PurposeTo quantitate the effect of verapamil administered orally, a calcium channel blocker and potent inhibitor of P‐glycoprotein on oral pharmacokinetics of the β1‐adrenergic receptor antagonist talinolol, a substrate of P‐glycoprotein.Subjects and MethodsIn a randomized, crossover placebo‐controlled study, oral pharmacokinetics of talinolol (50 mg) after concomitant administration of single doses ofR‐verapamil (120 mg) or placebo were investigated in 9 healthy volunteers. Concentrations of talinolol, verapamil, and its main metabolite norverapamil were measured in serum with HPLC. Concentrations of talinolol were also measured in urine by HPLC. Standard pharmacokinetic parameters were calculated with noncompartmental procedures.ResultsThe area under the concentration–time curve for talinolol from 0 to 24 hours was significantly decreased afterR‐verapamil versus placebo (721 ± 231 ng · h · mL−1versus 945 ± 188 ng · h · mL−1;P< .01). Maximum serum concentration of talinolol was reached significantly earlier afterR‐verapamil compared with placebo (P< .05). Coadministration ofR‐verapamil did not affect the renal clearance or half‐life of talinolol. Serum pharmacokinetics are paralleled by the results derived from urine concentrations of talinolol.ConclusionThis is the first study to show a decreased oral bioavailability of a P‐glycoprotein substrate (talinolol) in humans as a result of coadministration of verapamil. This effect is assumed to be caused by changes of the intestinal net absorption of talinolol because its renal clearance remains unaffected by administration ofR‐verapamil. This unexpected effect ofR‐verapamil is most likely dose dependent as a result of an interplay between intestinal P‐glycoprotein and gut metabolism.Clinical Pharmacology & Therapeutics(1999)65, 283–290; doi:
影响因子：
3.6
作者：
E. Schuetz;W. T. Beck;J. Schuetz
通讯作者：
E. Schuetz;W. T. Beck;J. Schuetz