Oxazepam esters. 2. Correlation of hydrophobicity with serum binding, brain penetration, and excretion

Abstract

Pharmacokinetics of a series of prodrug-type oxazepam esters [for tranquilizer and anticonvulsant use] were studied in mice. The effect of hydrophobicity was studied in relation to serum binding, brain penetration, tissue storage and excretion. Binding to mouse serum and to human serum albumin was measured by equilibrium dialysis, and the changes in binding free energy were correlated with RM values. Brain-blood partition of the esters did not change parallel with their serum binding. An indirect correlation exists between RM of the esters and oxazepam brain accrual. Brain-blood concentration ratios of oxazepam prove that hydrolysis precedes brain penetration and that hydrophobicity may primarily influence the hydrolysis rate. The amount of tissue storage and total excretion rates correlate with hydrophobicity.