Hydrophobic interactions responsible for unspecific binding of morphine-like drugs.

The unspecific binding of four narcotic analgesics 3H-dihydromorphine, 14C-morphine, 3H-etorphine and 3H-fentanyl to human albumin, human plasma, rabbit plasma and several tissue homogenates from rabbits was investigated using equilibrium dialysis and ultrafiltration. At a drug concentration of 10(-7) M in human plasma, dihydromorphine is bound to an extent of 14%, morphine to 23%, etorphine to 88% and fentanyl to 70%. These differences in binding are due to different degrees of hydrophobic interaction between the drugs investigated and the plasma or tissue components. The hydrophobic interactions are due to the unionized form of the drugs. The ionized form is bound to a negligible extent with all four compounds, possibly in part by ionic mechanism. Binding increased with increasing ionic strength of the protein solution, with raising temperature between 0 degrees C and 37 degrees C and with increasing pH values of the protein solution, features which are characteristic of hydrophobic interactions. Scatchard plots of the binding data, from which the total binding constants nk were derived, indicated high concentrations of binding sites compared with drug concentrations found analgesically effective in vivo.