Disposition kinetics and metabolism of omeprazole in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation recruited from an Oriental population.
To explore the relationship between omeprazole disposition and genetically determined S-mephenytoin 4'-hydroxylation phenotype status, we examined the kinetic variables of omeprazole and its two primary metabolites in plasma (5-hydroxyomeprazole and omeprazole sulfone) and the excretion profile of its principal metabolite in urine (5-hydroxyomeprazole) in eight extensive (EMs) and eight poor metabolizers (PMs) recruited from a Korean population. Each subject received a p.o. dose of 20 mg of omeprazole as an enteric-coated formulation, and blood and urine samples were collected up to 24 hr postdose. Omeprazole and its metabolites were measured by high-performance liquid chromatography with ultraviolet detection. The mean omeprazole area under the concentration-time curve (AUC), elimination half-life (T1/2) and apparent p.o. clearance were significantly (P less than .001) greater, longer and lower, respectively, in PMs than in EMs. The mean peak concentration and AUC of 5-hydroxyomeprazole and AUC ratio of 5-hydroxyomeprazole to omeprazole were significantly (P less than .01 to .001) less in PMs than in EMs. The mean peak plasma concentration, AUC of omeprazole sulfone and ratio of omeprazole sulfone to omeprazole were greater (P less than .001) and T1/2 was longer (P less than .001) in PMs than in EMs. The mean cumulative urinary excretion of 5-hydroxyomeprazole up to 24 hr postdose was significantly (P less than .001) less in PMs than in EMs. In addition, the log10 4'-hydroxymephenytoin excreted in urine correlated significantly (P less than .01) with the apparent p.o. clearance of omeprazole and half-lives of omeprazole, 5-hydroxyomeprazole and omeprazole sulfone.(ABSTRACT TRUNCATED AT 250 WORDS)
Sohn
D R
DR
Department of Pharmacology, College of Medicine, Gyeongsang National University, Chinju, Korea.
Kobayashi
K
K
Chiba
K
K
Lee
K H
KH
Shin
S G
SG
Ishizaki
T
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000284:Administration, Oral; D000328:Adult; D006801:Humans; D006900:Hydroxylation; D007723:Korea; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D009853:Omeprazole / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; C040450:omeprazole sulfone; C049963:5-hydroxymethylomeprazole; D009853:Omeprazole; D008617:Mephenytoin