Experimental comparing of lipophilicity of opioid antagonists

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.

1. Becker W.C., Fiellin D.A. When epidemics collide: Coronavirus disease. 2019 (covid-19) and the opioid crisis. Ann. Intern. Med. 2020; 173(1): 59–60. https://doi.org/ 10.7326/M20-1210

2. Skolnick P. Treatment of overdose in the synthetic opioid era. Pharmacol. Ther.; 2021; https://doi.org/10.1016/j.pharmthera.2021.108019

3. Burns S.M., Cunningham C.W., Mercer S.L. DARK Classics in Chemical Neuroscience: Fentanyl. ACS Chem. Neurosci.: Fentanyl; 2018; 9(10): 2428-37. https://doi.org/10.1021/acschemneuro.8b00174

4. Ujváry I., Christie R., Evans-Brown M., Gallegos A., Jorge R., Morais J., et al. DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles. ACS Chem. Neurosci. 2021; 12(7): 1072-92. https://doi.org/10.1021/acschemneuro.1c00037

5. Golovko A.I., Ivanov M.B., Rejnyuk V.L., Ivnickij Yu.Yu., Barinov V.A., Borodavko V.K. Toxicological characteristic of designer drugs from the group of synthetic opioids. Toksikologicheskij vestnik. 2019; 1(154): 3–11. (in Russian)

6. Bachmutsky I., Wei X.P., Kish E., Yackle K. Opioids depress breathing through two small brainstem sites. Elife. 2020; 9: e52694. https://doi.org/10.7554

7. Boyer E.W. Management of Opioid Analgesic Overdose. N. Engl. J. Med. 367(2): 146-55. https://doi.org/10.1056/NEJMra1202561

8. Armenian P., Vo K., Barr-Walker J., Lynch K. Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review. Neuropharmacology. 2018; 134(Pt A): 121-32. https://doi.org/10.1016

9. Volpe D.A., et al. Uniform assessment and ranking of opioid Mu receptor binding constants for selected opioid drugs. Regul. Toxicol. Pharmacol. 2011; 59(3): 385-90. https://doi.org/10.1016/j.yrtph.2010.12.007

10. Ujba V.V., Krivorotov D. V., Zabelin M.V., Radilov A.S., Rembovskij V.R., Dulov S.A., et al. Antagonists of opioid receptors. From the present to the future. Medicina ekstremal’nyh situacij. 2018; 20(3): 356–70. (in Russian)

11. Waterhouse R.N. Determination of lipophilicity and its use as a predictor of blood-brain barrier penetration of molecular imaging agents. Mol. Imaging Biol. 2003; 5(6): 376-89. https//doi.org/10.1016/j.mibio.2003.09.014

12. Kelly E., Sutcliffe K., Cavallo D., Ramos-Gonzalez N., Alhosan N., Henderson G. The anomalous pharmacology of fentanyl. Br. J. Pharmacol. 2021. https://doi.org/10.1111/bph.15573

13. Suzuki J., El-Haddad S. A review: Fentanyl and non-pharmaceutical fentanyls. Drug Alcohol Depend. 2017; 171: 107-16. https://doi.org/10.1016/j.drugalcdep.2016.11.033

14. Mather L.E. Clinical Pharmacokinetics of Fentanyl and its Newer Derivatives. Clin. Pharmacokinet. 1983; 8(5): 422-46. https://doi.org/10.2165/00003088-198308050-00004

15. Hill R., Santhakumar R., Dewey W., Kelly E., Henderson G. Fentanyl depression of respiration: Comparison with heroin and morphine. Br. J. Pharmacol. 2020; 177(2): 254-66. https://doi.org/10.1111/bph.14860

16. Rogers R.D., Willauer H.D., Griffin S.T., Huddleston J.G. Partitioning of small organic molecules in aqueous biphasic systems. J. Chromatogr. B. Biomed. Sci. Appl. 1998; 711(1-2): 255-63. https://doi.org/10.1016/s0378-4347(97)00661-0

17. Andrés A., Rosés M., Ràfols C., Bosch E., Espinosa S., Segarra V. , et al. Setup and validation of shake-flask procedures for the determination of partition coefficients (logD) from low drug amounts. Eur. J. Pharm. Sci. 2015; 76: 181-91. https://doi.org/10.1016/j.ejps.2015.05.008

18. Kaufmann J.J., Koski W.W., Benson D.N., Semo N.M. Narcotic and narcotic coefficients antagonist pKa’s and partition coefficients and their significance in clinical practice. Drug Alcohol Depend. 1975; 1(2): 103-14. https//doi.org/10.1016/0376-8716(75)90012-5

19. Janicka M., Sztanke M., Sztanke K. Reversed-phase liquid chromatography with octadecylsilyl, immobilized artificial membrane and cholesterol columns in correlation studies with in silico biological descriptors of newly synthesized antiproliferative and analgesic active compounds. J. Chromatogr. A. 2013; 1318: 92-101. https://doi.org/10.1016/j.chroma.2013.09.060

20. Haymerle A., Fahlman Å., Walzer C. Human exposures to immobilising agents: Results of an online survey. Vet. Rec. 2010; 167(9): 327-32. https://doi.org/10.1136/vr.c4191

21. Database of chemical molecules and their activities against biological assays. https://pubchem.ncbi.nlm.nih.gov/ (accessed 05.02.2022).