Potential of lansoprazole as a novel probe for cytochrome P450 3A activity by measuring lansoprazole sulfone in human liver microsomes.
Cytochrome P450 (CYP) 3A enzymes are responsible for the metabolism of many drugs. It is useful to know CYP3A activity in individual patients undergoing drug therapy so as to predict the efficacies or adverse events. Lansoprazole is metabolized to Lansoprazole sulfone (LS) by CYP3A, while to 5-hydroxylansoprasole by CYP2C19. The aim of this study was to evaluate whether lansoprazole can be used to assess CYP 3A activity in human liver. Lansoprazole sulfoxidation activity in 14 human liver microsomes was determined as the ratio of lansoprazole/LS, measuring these parameters by high-performance liquid chromatography. Testosterone 6beta-hydroxylation (T6beta-OH) activity, a known marker for CYP3A activity was also measured together with lansoprazole sulfoxidation activity. Lansoprazole sulfoxidation activity was also analyzed in microsomes preincubat-ed with anti-CYP2C19 antibody. Interindividual variation was observed in lansoprazole sulfoxidation activity and T6beta-OH activities of those microsomes, respectively. Lansoprazole sulfoxidation activity was significantly correlated with T6beta-OH activity and CYP3A protein level. Lansoprazole sulfoxidation activity in microsomes with anti-CYP2C19 antibody was closely correlated with T6beta-OH activity. In contrast, lansoprazole 5-hydroxylation activity was correlated with the CYP2C19 activity. These results suggest that metabolism of lansoprazole to LS by CYP3A occurs independently of metabolism by CYP2C19. LS can be used as a new marker of CYP3A activity.
Yanagida
Yohei
Y
Department of Pharmacology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Watanabe
Minoru
M
Takeba
Yuko
Y
Kumai
Toshio
T
Matsumoto
Naoki
N
Hayashi
Mikihito
M
Suzuki
Satoshi
S
Kinoshita
Yuichi
Y
Kobayashi
Shinichi
S
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000032:analysis* / Q000493:pharmacokinetics; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D064747:Lansoprazole; D050216:Metabolic Detoxication, Phase I; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D015335:Molecular Probes / Q000032:analysis* / Q000493:pharmacokinetics; D013250:Steroid Hydroxylases / Q000378:metabolism; D013450:Sulfones / Q000032:analysis / Q000493:pharmacokinetics
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000911:Antibodies, Monoclonal; D015335:Molecular Probes; D013450:Sulfones; D064747:Lansoprazole; D003577:Cytochrome P-450 Enzyme System; C581535:Lansoprazole Sulfone; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase