MEASUREMENT OF LIPOPHILICITY INDEXES BY REVERSED-PHASE HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY - COMPARISON OF 2 STATIONARY PHASES AND VARIOUS ELUENTS

Twenty-eight benzene derivatives spanning a broad range of lipophilicities were used as model compounds to examine the optimum stationary phase and eluent conditions for the determination of lipophilic indices by reversed-phase high-performance liquid chromatography. This was assessed by linear regressions comparing published octanol-water partition coefficients with isocratic capacity factors and capacity factors extrapolated to 100% water in the eluent. Methanol-water eluents are always to be preferred to acetonitrile-water and tetrahydrofuran-water eluents. The octadecylsilane (ODS) phase yielded good correlations especially when a masking agent was added to the eluent, but this introduced an additional experimental variable. The octadecyl-polyvinyl copolymer (ODP) phase was just as satisfactory as the ODS phase without the need for a masking agent, and thus appears to be a valuable alternative

Morphine 6-Glucuronide and Morphine 3-Glucuronide As Molecular Chameleons with Unexpected Lipophilicity

Morphine 6-glucuronide, but not morphine 3-glucuronide, is a highly potent opiate receptor agonist. In fact, there is converging evidence that much of the analgesic effect occurring after morphine treatment in humans is due to this metabolite rather than to the parent drug. Yet glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier and rapidly excreted by the urinary and/or biliary routes. Here, we report that morphine 6-glucuronide, and to a lesser extent morphine 3-glucuronide, are far more lipophilic than predicted, and in fact not much less lipophilic than morphine itself. Force-field and quantum mechanical calculations indicate that the two glucuronides can exist in conformational equilibrium between extended and folded forms. The extended conformers, because they efficiently expose their polar groups, must be highly hydrophilic forms predominating in polar media such as water; in contrast, the folded conformers mask part of their polar groups, thus being more lipophilic and likely to predominate in media of low polarity such as biological membrane