Prediction of hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit based on quantitative structure—Pharmacokinetic relationships

Abstract

Based on the concept of physiological pharmacokinetics, the hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit was predicted based on the relationships between principle kinetic parameters and lipophilicity (chloroform-water partition coefficient). Good log-log linear relationships between kinetic parameters and lipophilicity were obtained for the seven barbiturates examined. The values of correlation coefficient were improved slightly by using the corrected values for partition coefficients of nonionic molecules in the cases of principle parameters such as drug-protein and drug-blood cell affinity, intrinsic hepatic clearance, and unbound volume of distribution. There was also a good linear relationship between absorption rate constant (mean absorption time) and lipophilicity. The mean hepatic transit time was negligible for the most lipophilic drug (hexobarbital) examined; this suggests that the mean absorption time for these barbiturates does reflect the absorption process. The available fraction in relation to hepatic first-pass metabolism was well predicted from the lipophilicity by both well-stirred and parallel-tube models, and the difference in the values predicted by both models was minimal. There were good relationships between predicted and observed values for plasma levels after intravenous and oral administration, except for two (cyclobarbital and phenobarbital) of the seven drugs used. The great difference between predicted and observed values for these two drugs was considered due to substituent effects in liver metabolism.