Metabolic disposition of lansoprazole in relation to the S-mephenytoin 4'-hydroxylation phenotype status.
OBJECTIVE
To assess the possible involvement of CYP2C19 in the metabolism of lansoprazole in vivo.


METHODS
Sixteen male Korean subjects, who had been phenotyped as extensive metabolizers and poor metabolizers of S-mephenytoin 4'-hydroxylation polymorphism (n = 8 each) with racemic mephenytoin with use of the 8-hour urine analysis of 4'-hydroxymephenytoin, took an oral dose of 30 mg lansoprazole, and blood samples were collected up to 48 hours after dosing. Lansoprazole and its metabolites were measured by high-performance liquid chromatography with ultraviolet detection.


RESULTS
The mean lansoprazole area under the concentration-time curve (AUC), elimination half-life (t1/2), and apparent oral clearance (CLoral) were significantly (p < 0.001) greater, longer, and lower, respectively, in the poor metabolizer than in the extensive metabolizer group. The mean values for the AUC of hydroxylansoprazole and AUC ratio of hydroxylansoprazole to lansoprazole were significantly (p < 0.01 to p < 0.001) less in the poor metabolizer than in the extensive metabolizer group, whereas those for the AUC of lansoprazole sulfone and ratio of lansoprazole sulfone to lansoprazole were greater (p < 0.001) in the former than in the latter group. In addition, the log10 4'-hydroxymephenytoin excreted in urine correlated significantly (p < 0.01) with the CLoral of lansoprazole.


CONCLUSIONS
These results suggest that the hydroxylation of lansoprazole cosegregates with the genetically determined S-mephenytoin 4'-hydroxylation (CYP2C19) polymorphism in the Korean subjects.
Sohn
D R
DR
Department of Clinical Pharmacology, Soonchunhyang University College of Medicine, Chonan, Republic of Korea. drsohn@asan.sch.ac.kr
Kwon
J T
JT
Kim
H K
HK
Ishizaki
T
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000284:Administration, Oral; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D006900:Hydroxylation; D007723:Korea; D064747:Lansoprazole; D008297:Male; D008617:Mephenytoin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009853:Omeprazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000652:urine; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D054328:Proton Pump Inhibitors
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D003577:Cytochrome P-450 Enzyme System; C581535:Lansoprazole Sulfone; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D008617:Mephenytoin