In vitro hydrolysis of polyunsaturated fatty acid N-acyloxymethyl derivatives of theophylline

Abstract A series of fatty acid N -acyloxymethyl derivatives of theophylline was prepared to determine the effects of varying the nature of the fatty acid on their in vitro rates of hydrolysis using porcine liver esterase and human plasma. The carboxylic acids examined include acetic (Ac), valeric (VA), nonanoic (NA), stearic (SA), oleic (OA), linoleic (LA), γ -linolenic (GLA), α -linolenic (ALA), eicosapentaenoic (EPA), elaidic (EA) and linoelaidic acid (LEA). When exposed to porcine liver esterase the NA acid derivative was hydrolyzed about 80 times faster than the triple bond GLA and ALA derivatives, which were hydrolyzed about four times as fast as the double bond LA derivative, which was hydrolyzed three times as fast as the single bond OA derivative. In human plasma the VA acid derivative was hydrolyzed over 100 times faster than the GLA derivative. Both the trans fatty acid EA and LEA derivatives were hydrolyzed slower than their cis counterparts. In both porcine esterase and human plasma, the derivatives displayed the classical parabolic relationship when the logarithm of the rate constant, k , was plotted versus the lipophilicity index, log K. Although the unsaturated fatty acid derivatives with three or more double bonds are not hydrolyzed at the maximum rate, they are hydrolyzed at markedly faster rates than the corresponding saturated or mono-unsaturated derivatives and as such still may serve as a delivery vehicle for other drugs.