ObjectiveTo evaluate the enantioselective disposition of lansoprazole in relation to the genetic polymorphism of CYP2C19.MethodsA single oral dose of racemic lansoprazole (30 mg) was administered to6 extensive metabolizers and 6 poor metabolizers whose genotypes were determined by use of polymerase chain reaction‐restriction fragment length polymorphism. The pharmacokineticparameters were estimated from the plasma concentrations of lansoprazole racemate, its enantiomers, and metabolites, which were measured for 24 hours after drug administration. The unbound fraction of lansoprazole enantiomers was determined by means of ultrafiltrationof fresh human serum spiked with racemic lansoprazole.ResultsThe plasma concentrations of R(+)‐lansoprazole were consistently higher than those of the S(−)‐enantiomer in both extensive and poor metabolizers of CYP2C19, and the meanarea under the plasma concentration‐time curve of the (+)‐ and (−)‐enantiomersshowed 4.3‐ and 5.8‐fold differences between poor and extensive metabolizers, respectively. The (+)/(−) ratios of lansoprazole clearance were not significantly different betweenpoor and extensive metabolizers (0.19 ± 0.07 and 0.05 ± 0.08, respectively). The values for volume of distribution of the (−)‐enantiomer were 3‐ and 10‐fold greater, respectively, than those of the (+)‐enantiomer in poor and extensive metabolizers, which was related to a 2‐fold higher unbound fraction of the (−)‐enantiomer.ConclusionsThe effect of CYP2C19 genetic polymorphism on the enantioselectivedisposition of lansoprazole seems to be less significant than the effect on omeprazole and pantoprazole. The disposition of lansoprazole enantiomers appears to be influenced by enantioselective protein binding and by enantioselective metabolism of lansoprazole.Clinical Pharmacology & Therapeutics (2002) 72, 90–99; doi: 10.1067/mcp.2002.126176