Octanol−, Chloroform−, and Propylene Glycol Dipelargonat−Water Partitioning of Morphine-6-glucuronide and Other Related Opiates

• Published in: Journal of medicinal chemistry Vol. 39; no. 22; pp. 4377 - 4381
• Main Authors: Avdeef, Alex, Barrett, David A, Shaw, P. Nicholas, Knaggs, Roger D, Davis, Stanley S
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 25.10.1996
• Subjects: Biological and medical sciences; Biological Transport; Chemical Phenomena; Chemistry, Physical; Chloroform; General pharmacology; Hydrogen-Ion Concentration; Medical sciences; Morphine Derivatives - chemistry; Narcotics - chemistry; Octanols; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Potentiometry; Solutions; Solvents; Morphine derivatives; Chloroform; Metabolite; Octanol; Lipophily; Opiates; Partition coefficient; Narcotic analgesic; Glucuroconjugate; Ethylene oxide polymer; Alkaloid; Uronic acid; Glycoside; Physicochemical properties
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960073m

The pK a and log P values of morphine-6-β-d-glucuronide (M6G) and morphine-3-β-d-glucuronide (M3G) and a range of structurally-related opiates (morphine, normorphine, codeine, norcodeine, 6-acetylmorphine, diacetylmorphine, and buprenorphine) were accurately measured using a potentiometric approach. The measured lipophilicity profiles (pH 2−11, 0.15 M KCl matrix) of M3G and M6G were compared using a proton donor solvent (chloroform) and a proton acceptor solvent (propylene glycol dipelargonate, PGDP), in addition to octanol. The log P values and lipophilicity profiles of M6G and M3G determined in octanol−water have confirmed the unexpectedly high lipophilicity of the two glucuronides. These results show the importance of measuring the effect of pH on lipophilicity, since log D (pH 7.4) values gave a notably different order of lipophilicity for the opiates compared with log P. M6G, but not M3G, showed significant differences in log P between different types of partitioning solvents. The observed order of lipophilicities (log D, pH 7.4) was buprenorphine (3.93), diacetylmorphine (0.85), 6-acetylmorphine (0.61), codeine (0.22), morphine (−0.07), M6G (−0.79), M3G (−1.12), norcodeine (−1.26), and normorphine (−1.56).