Ablation of Both Organic Cation Transporter (Oct)1 and Oct2 Alters Metformin Pharmacokinetics but Has No Effect on Tissue Drug Exposure and Pharmacodynamics
Ablation of Both Organic Cation Transporter (Oct)1 and Oct2 Alters Metformin Pharmacokinetics but Has No Effect on Tissue Drug Exposure and Pharmacodynamics
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DOI：
10.1124/dmd.112.044875
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发表时间：
2012-06-01
影响因子：
3.9
通讯作者：
Zamek-Gliszczynski, Maciej J.
中科院分区：
文献类型：
--
作者：
Higgins, J. William;Bedwell, David W.;Zamek-Gliszczynski, Maciej J.
有机阳离子转运蛋白（OCT）1和OCT 2分别介导二甲双胍的肝脏摄取和分泌性肾脏清除。尚未直接研究两种转运蛋白同时受损的药代动力学/药效学（PK/PD）影响，例如全身性泛OCT抑制。目前，在Oct 1/Oct 2基因敲除小鼠中研究了二甲双胍的PK/PD、分布和排泄。在Oct 1/Oct 2基因敲除小鼠中，从肾血流量到未结合肾小球滤过率的代谢物清除率降低了4.5倍，分布容积降低了3.5倍。口服生物利用度不受影响（F = 64 +/- 4 vs 59 +/- 11;敲除vs野生型）。在Oct 1/Oct 2基因敲除小鼠中，肝脏和肾脏与血浆的浓度比分别降低了4.2倍和2.5倍。口服二甲双胍暴露量增加2.9倍和组织分配减少导致组织药物浓度几乎没有净变化。绝对肾脏暴露量不变（敲除/野生型= 1.1 +/- 0.2），肝脏暴露量仅适度降低（敲除/野生型= 0.6 +/- 0.1）。在检测的5个剂量水平下，Oct 1/Oct 2基因敲除小鼠中二甲双胍降低口服葡萄糖曲线下面积（AUC）的作用未受损（ED 50 = 151 vs 110 mg/kg;最高剂量下的葡萄糖降低= 42 +/- 1 vs 39 +/- 4%;敲除vs野生型）;然而，在基因敲除小鼠中需要更高的二甲双胍全身暴露量以引起相同的效果（半数最大有效AUC = 70 vs 26 μ g.h/ml）。尽管Oct 1/Oct 2基因敲除小鼠的二甲双胍清除率和分布容积发生了重大变化，但组织药物暴露和PD未受到影响。这些发现挑战了全身OCT抑制会影响二甲双胍药理学的假设。
Organic cation transporter (OCT)1 and OCT2 mediate hepatic uptake and secretory renal clearance of metformin, respectively. Pharmacokinetic/pharmacodynamic (PK/PD) implications of simultaneous impairment of both transporters, such as by systemic pan-OCT inhibition, have not been studied directly. At present metformin PK/PD, distribution, and excretion were studied in Oct1/Oct2-knockout mice. Metformin clearance was reduced 4.5-fold from renal blood flow to unbound glomerular filtration rate, and volume of distribution was reduced 3.5-fold in Oct1/Oct2-knockout mice. Oral bioavailability was not affected (F = 64 +/- 4 versus 59 +/- 11; knockout versus wild type). Liver- and kidney-to-plasma concentration ratios were decreased in Oct1/Oct2-knockout mice 4.2- and 2.5-fold, respectively. The 2.9-fold increase in oral metformin exposure and reduced tissue partitioning yielded little to no net change in tissue drug concentrations. Absolute kidney exposure was unchanged (knockout/wild type = 1.1 +/- 0.2), and liver exposure was only modestly decreased (knockout/wild type = 0.6 +/- 0.1). Oral glucose area under the curve (AUC) lowering by metformin was not impaired in Oct1/Oct2-knockout mice at the five dose levels tested (ED50 = 151 versus 110 mg/kg; glucose lowering at highest dose = 42 +/- 1 versus 39 +/- 4%; knockout versus wild type); however, higher systemic metformin exposures were necessary in knockout mice to elicit the same effect (half-maximal efficacious AUC = 70 versus 26 mu g.h/ml). Despite major changes in metformin clearance and volume of distribution in Oct1/Oct2-knockout mice, tissue drug exposure and PD were not affected. These findings challenge the presumption that systemic OCT inhibition will affect metformin pharmacology.