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). † Contribution no. 7 in the pH-Metric logP series from Sirius. Reference 25 is part 6; ref 26 is part 8.
Purified mussel adhesive protein mefp-1 (Mytilus edulis foot protein 1) has been studied regarding its state of oligomerization and gross conformation in dilute solution. Sedimentation equilibrium in the analytical ultracentrifuge of a dilute solution of protein (0.4 mg/mL) in acetate buffer at pH 4.5 and I = 0.10 M yielded an apparent molecular weight (whole distribution weight average, Mw, app) of 114 000 +/- 5000 via the "M" procedure, a value in almost exact agreement with the monomeric molecular weight obtained by MALDI mass spectrometry. At this low concentration, it is reasonable to assume thermodynamic ideality, i.e., Mw,app approximately Mw. This result, together with plots of point weight average apparent molecular weight versus concentration for three different loading concentrations (0.4, 0.8, 1.0 mg/mL), clearly demonstrates that this protein is essentially monomeric in dilute solution. Sedimentation velocity experiments yielded an estimate of the sedimentation coefficient s020,w = 2.34 +/- 0.17 S, which for M = 110 000 gives a frictional ratio f/f0 = 3.2 +/- 0.3. The interpretation of this, in terms of an extended rather than globular conformation for the structure of mefp-1 in dilute solution, is considered, within plausible limits of molecular hydration, and models for the structure in solution are considered, in light of the thermodynamic nonideality behavior of these molecules and previously published circular dichroism data. The significance of these observations in terms of the bioadhesive properties of mefp-1 is described, and the very strong interaction in dilute solution with a mucin glycoprotein is demonstrated.
The toxicity of a number of solubilized or colloidal amphotericin B formulations to human erythrocytes has been studied in-vitro. All the solubilized formulations studied, using poloxamer F127 or L92, or sodium deoxycholate as solubilizing agents, showed similar toxicity, erythrocyte lysis being greater than 90% for amphotericin B concentrations between 4 to 8 micrograms mL-1. Emulsion formulations stabilized by poloxamers showed reduced toxicity, while those stabilized by egg lecithin showed less than 5% erythrocyte lysis up to an amphotericin B concentration of 200 micrograms mL-1. The mechanisms of the differential toxicity is considered to be due to the differences in the equilibrium concentration of free amphotericin B in the aqueous phase.
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