Long-acting κ opioid antagonists nor-BNI, GNTI and JDTic: pharmacokinetics in mice and lipophilicity.
Long-acting κ opioid antagonists nor-BNI, GNTI and JDTic: pharmacokinetics in mice and lipophilicity.
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DOI：
10.1186/1471-2210-12-5
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发表时间：
2012-05-29
期刊：
影响因子：
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通讯作者：
Cohen BM
中科院分区：
文献类型：
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作者：
Munro TA;Berry LM;Van't Veer A;Béguin C;Carroll FI;Zhao Z;Carlezon WA Jr;Cohen BM
no - bni、GNTI和JDTic诱导κ阿片样物质拮抗作用延迟数小时，可持续数月。其他影响是暂时的。有人提出，这些药物可能被缓慢吸收或分布，并可能溶解在细胞膜中，从而减缓消除和延长其作用。最近的证据表明，相反，它们诱导κ阿片受体的长时间脱敏。为了验证这些假设，我们测量了non - bni、GNTI和JDTic的相关理化性质，以及腹腔给药后小鼠脑和血浆浓度的时间（采用LC-MS-MS）。在每个病例中，血药浓度在30分钟内达到最大值，并在4小时内下降80%，与先前报道的短暂效应密切相关。血浆水平与κ拮抗剂的延迟和延长时间之间存在明显的负相关。脑内非bni和JDTic水平在30分钟内达到峰值，但非bni在数小时内基本消除，JDTic在一周内逐渐下降。大脑对GNTI的吸收太低，无法准确测量，而更高的剂量被证明是致命的。没有一种药物是高度亲脂性的，表现为高水溶性（> 45 mM）和低辛醇分布（log D7.4 < 2）。脑匀浆结合在许多短效药物的范围内（bbb7%未结合）。JDTic表现为p- gp介导的外排；而BNI和GNTI则没有，但它们的低游离脑摄取表明外排是由另一种机制引起的。我们观察到的负血浆浓度-效应关系很难与简单的竞争拮抗相协调，但与脱敏一致。令人惊讶的是，在这些条件下，JDTic经历了主动外排，对匀浆有适度的亲和力，并且作用时间比非bni短。我们认为这种持久性可能是由于在溶酶体等细胞室中被困住。
Nor-BNI, GNTI and JDTic induce κ opioid antagonism that is delayed by hours and can persist for months. Other effects are transient. It has been proposed that these drugs may be slowly absorbed or distributed, and may dissolve in cell membranes, thus slowing elimination and prolonging their effects. Recent evidence suggests, instead, that they induce prolonged desensitization of the κ opioid receptor. To evaluate these hypotheses, we measured relevant physicochemical properties of nor-BNI, GNTI and JDTic, and the timecourse of brain and plasma concentrations in mice after intraperitoneal administration (using LC-MS-MS). In each case, plasma levels were maximal within 30 min and declined by >80% within four hours, correlating well with previously reported transient effects. A strong negative correlation was observed between plasma levels and the delayed, prolonged timecourse of κ antagonism. Brain levels of nor-BNI and JDTic peaked within 30 min, but while nor-BNI was largely eliminated within hours, JDTic declined gradually over a week. Brain uptake of GNTI was too low to measure accurately, and higher doses proved lethal. None of the drugs were highly lipophilic, showing high water solubility (> 45 mM) and low distribution into octanol (log D7.4 < 2). Brain homogenate binding was within the range of many shorter-acting drugs (>7% unbound). JDTic showed P-gp-mediated efflux; nor- BNI and GNTI did not, but their low unbound brain uptake suggests efflux by another mechanism. The negative plasma concentration-effect relationship we observed is difficult to reconcile with simple competitive antagonism, but is consistent with desensitization. The very slow elimination of JDTic from brain is surprising given that it undergoes active efflux, has modest affinity for homogenate, and has a shorter duration of action than nor-BNI under these conditions. We propose that this persistence may result from entrapment in cellular compartments such as lysosomes.