Shabbir Anik

Absorption and metabolism of nafarelin, a potent agonist of gonadotropin-releasing hormone

Nafarelin, a potent gonadotropin—releasing hormone (GnRH) agonist, was absorbed rapidly into systemic circulation (time to reach peak concentration, 20 to 40 minutes) after intranasal but not after sublingual or vaginal administration. Serum elimination half‐life was about 2 hours. Nasal absorption of nafarelin was increased by increasing the concentration of the drug in the dose solution and incorporating sodium glycocholate into the nasal formulation. An optimal formulation providing maximum nasal absorption of nafarelin was one containing 1.75 mg nafarelin per ml and 2% sodium glycocholate. Bioavailability of this nasal formulation relative to a single subcutaneous dose averaged 21%. The metabolism and excretion of nafarelin were determined in three subjects after subcutaneous administration of [14C]‐nafarelin. Radioactivity was excreted in approximately equal amounts in urine and stool. Six metabolites accounted for most of the radioactivity in urine. Four metabolites were short peptide fragments of nafarelin and the other metabolites were naphthylalanine and 2‐naphthylacetic acid.

The solvent contribution to the free energy of protein-ligand interactions

Abstract The intrinsic solvent contribution to the free energy of protein-ligand interactions in solution is shown to be related to a free energy per unit area term, obtained from analysis of the solution to gas phase process, and the change in accessible area on association. Analysis of the free energy data on a per unit area basis for the solution to gas phase process leads to the conclusion that the aliphatic CH2 group is only slightly intrinsically hydrophobic, δΔG°/ A 2 = 6 cal mol −1 A 2 , whereas the aromatic compound are actually intrinsically hydrophilic, δΔG°/ A 2 = -26 cal mol −1 A 2 . This leads to the conclusion that, for the interaction of benzene, naphthalene and anthracene with the binding site of α-chymotrypsin, the ligand-solvent free energy contribution is actually unfavorable. Since the protein-solvent contribution is small or unfavorable, the central conclusion is that the solvent contribution to protein-ligand interactions is small or unfavorable and that it is the protein-ligand non-bonded interactions that provide the driving force for association.