Experimental comparing of lipophilicity of opioid antagonists

D. Krivorotov, Dmitrij Mikhajlovich Kochura, S. Dulov, Andrej Stanislavovich Radilov
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Abstract

Introduction. The high lipophilicity of synthetic opioids determines their abnormally high toxicity in comparison with natural opiates. The need to develop medical treatment of poisoning with such substances validates the task to study experimentally the logP partition coefficients of narcotic analgesics and their antagonists in standardized conditions close to the conditions of a living organism. Material and methods. The lipophilicity of pharmacological agents was determined in accordance with the principles of GOST 32474-2013. “Methods of testing chemical products that pose a threat to the environment. The determination of the n-octanol/water partition coefficient by high-performance liquid chromatography”, using the selected calibration dependence of the lipophilicity values on the logarithm of the retention factor of the substances studied. Results. The HPLC method has been proposed to determine the logP value of opioid antagonists using selected reference pharmacological agents. The method has revealed a linear dependence of the logP of CNS-active pharmacological agents on the logarithm of their retention factor in the chromatographic column, which allowed to determine the logP value of a number of opioid receptor antagonists and a model representative of synthetic opioids in one experiment. Limitations. The calibration dependence of the lipophilicity value on the logarithm of the retention factor of the studied substances has been obtained using reference logP values of a limited number of reference substances. Conclusion. When conducting pharmacological studies, using the HPLC method for the definition of logP provides high reproducibility of measurement conditions close to the conditions of a living organism and allows to compare the results obtained. Thus, the correlation of the logP values, found by the HPLC method, has showed a ten times lower lipophilicity of naloxone relative to fentanyl. The largest value of logP, among the studied opioid receptor antagonists used in clinical practice, was found for nalmefene.
阿片拮抗剂亲脂性的实验比较
介绍。与天然阿片类药物相比,合成阿片类药物的高亲脂性决定了它们异常高的毒性。开发此类物质中毒的医学治疗方法的必要性,验证了在接近活体条件的标准化条件下实验研究麻醉性镇痛药及其拮抗剂的logP分割系数的任务。材料和方法。药物的亲脂性按照GOST 32474-2013的原则进行测定。“检测对环境构成威胁的化学产品的方法。用“高效液相色谱法”测定正辛醇/水分配系数,采用选择的校准依赖于所研究物质的亲脂性值的保留系数的对数。结果。采用高效液相色谱法测定阿片拮抗剂的logP值。该方法揭示了中枢神经系统活性药物的logP与其色谱柱中保留因子的对数呈线性依赖关系,从而可以在一个实验中确定许多阿片受体拮抗剂和合成阿片的模型代表的logP值。的局限性。利用有限数量的参考物质的logP值,得到了所研究物质的亲脂性值与保留因子的对数的校准依赖关系。结论。在进行药理学研究时,使用高效液相色谱法定义logP提供了接近活体条件的测量条件的高再现性,并允许对所获得的结果进行比较。因此,通过高效液相色谱法发现的logP值的相关性表明,纳洛酮的亲脂性比芬太尼低10倍。在临床使用的阿片受体拮抗剂中,logP值最大的是纳美芬。
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