Stereoselective Metabolism of Lansoprazole by Human Liver Cytochrome P450 Enzymes

Kim, Kyoung Ah; Kim, Min Jung; Park, Ji Young; Shon, Ji‐Hong; Yoon, Young Cheol; Lee, Sang Seop; Liu, Kwang-Hyeon; Chun, Jin Ho; Hyun, Myung Ho; Shin, Jae Gook

doi:10.1124/dmd.31.10.1227

Cited by 62 publications

(50 citation statements)

References 19 publications

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“…Substrates were used at concentrations approximately equal to their respective K m values: 15 M for diclofenac, 50 M for phenytoin, 50 M for tolbutamide, and 5 M for S-warfarin. After preincubation, reactions were initiated at 37°C by addition of the NADPH-generating system (3.3 mM glucose 6-phosphate, 1.3 mM ␤-NADP ϩ , 3.3 mM MgCl 2 , and 1.0 unit/ml glucose-6-phosphate dehydrogenase) and stopped after the specified time by placing the incubation tubes on ice and adding 100 l of either ice-cold acetonitrile or 10% perchloric acid, depending on the reaction, as described previously (Bourrie et al, 1996;Shin et al, 1999, Kim et al, 2003. Incubation mixtures were centrifuged at 20,000g for 10 min at 4°C, and aliquots of the supernatants were analyzed by HPLC.…”

Section: Methodsmentioning

confidence: 99%

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Lansoprazole Enantiomer Activates Human Liver Microsomal Cyp2c9 Catalytic Activity in a Stereospecific and Substrate-Specific Manner

Liu

Kim²,

Jung

et al. 2004

Drug Metab Dispos

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ABSTRACT:We recently proposed a possible stereoselective activation by lansoprazole of CYP2C9-catalyzed tolbutamide hydroxylation, as well as stereoselective inhibition of several cytochrome P450 (P450) isoforms. This study evaluated the effects of lansoprazole enantiomers on CYP2C9 activity in vitro, using several probe substrates. For tolbutamide 4-methylhydroxylation and phenytoin 4-hydroxylation, Rlansoprazole was an activator (140 and 550% of control at 100 M R-lansoprazole, EC 50 values of 19.9 and 30.2 M, respectively). RLansoprazole-mediated activation of the formation of 4-hydroxyphenytoin was also seen with recombinant human CYP2C9. R-Lansoprazole increased the Michaelis-Menten-derived V max of phenytoin 4-hydroxylation from 0.024 to 0.121 pmol/min/pmol P450, and lowered its K m from 20.5 to 15.0 M, suggesting that R-lansoprazole activates CYP2C9-mediated phenytoin metabolism without displacing phenytoin from the active site. Kinetic parameters were also estimated using the two-site binding equation, with ␣ values <1 and ␤ values >1, indicative of activation. Additionally, phenytoin at 10 to 200 M had no reciprocal effect on the hydroxylation of R-lansoprazole. Meanwhile, R-lansoprazole had no activation effect on diclofenac and S-warfarin metabolism in the incubation study using both recombinant CYP2C9 and human liver microsomes. These substratedependent activation effects suggest that phenytoin has a different binding orientation compared with diclofenac and S-warfarin. Overall, these results suggest that R-lansoprazole activates CYP2C9 in a stereospecific and substrate-specific manner, possibly by binding within the active site and inducing positive cooperativity. This is the first report to describe stereoselective activation of this cytochrome P450 isoform.

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Section: Methodsmentioning

confidence: 99%

“…Lansoprazole at therapeutic concentrations is metabolized, mainly by CYP2C19 and CYP3A4, to its hydroxy and sulfone metabolites, respectively, and is also metabolized by CYP2C9 to hydroxylansoprazole (Kim et al, 2002(Kim et al, , 2003. Recently, we found that lansoprazole caused stereoselective inhibition of several P450 isoforms.…”

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confidence: 99%

Lansoprazole Enantiomer Activates Human Liver Microsomal Cyp2c9 Catalytic Activity in a Stereospecific and Substrate-Specific Manner

Liu

Kim²,

Jung

et al. 2004

Drug Metab Dispos

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“…6). For this, we normalized the metabolic rates of the expressed P450 isoforms according to the abundance of the respective isoforms in the human liver, as described by Rodrigues (36) or Kim et al (37). Briefly, the reaction rates measured with individual cDNA-expressed P450 isoforms were normalized with respect to the nominal specific content of the corresponding P450 in native human liver microsomes.…”

Section: Resultsmentioning

confidence: 99%

CYP2J2 and CYP2C19 Are the Major Enzymes Responsible for Metabolism of Albendazole and Fenbendazole in Human Liver Microsomes and Recombinant P450 Assay Systems

Lee

Joo

et al. 2013

Antimicrob Agents Chemother

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e Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 l/min/pmol P450, which is a rate 3.9-and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 l/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7-and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazole in vivo.A lbendazole and fenbendazole are benzimidazole compounds used as broad-spectrum anthelmintics against gastrointestinal nematodes and the larval stages of cestodes (1). Benzimidazole anthelmintics are extensively metabolized in domestic animals and humans. Animal and microsomal incubation studies have demonstrated rapid conversion of albendazole and fenbendazole to a sulfoxide metabolite and subsequently a sulfone metabolite (2-6). Sulfoxide metabolites are responsible for the systemic biological activity of benzimidazole drugs (7). Their metabolic patterns and the resultant pharmacokinetic behaviors are relevant in the attainment of high and sustained concentrations of pharmacologically active drugs/metabolites at the target parasite (8). Evidence from microsomal investigations in a number of species suggests that CYP3A4 and flavin-containing monooxygenase (FMO) are major enzymes responsible for the formation of sulfoxide metabolites from albendazole (4, 9, 10) and fenbendazole (4, 5) (Fig. 1). Recently, Lee et al. (11) reported that the rates of albendazole sulfoxide formation from albendazole by the recombinant CYP2J2 (rCYP2J2) isoform were signifi...

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“…25) We focused on the metabolic pathway of lansoprazole, which is metabolized almost equally to LS and 5-hydroxylansoprazole by CYP3A and CYP2C19, respectively, which means the contribution of CYP3A4 on lansoprazole metabolism by CYP3A is greater than that of omeprazole. 26) Moreover, it will be important that this metabolic pathway of lansoprazole can be said simple among many PPIs. There are few reports of serious adverse events associated with lansoprazole in various patient populations.…”

Section: Discussionmentioning

confidence: 99%

Potential of Lansoprazole as a Novel Probe for Cytochrome P450 3A Activity by Measuring Lansoprazole Sulfone in Human Liver Microsomes

Yanagida

Watanabe

Takeba

et al. 2009

Biological & Pharmaceutical Bulletin

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Cytochrome P450 (CYP) 3A is the primary CYP isoenzyme subfamily responsible for phase I metabolism of Ͼ50% of drug doses administered to humans.1,2) CYP3A4 is the most prominent CYP in humans, comprising about 30% and 70% of total CYP in the liver and intestine, respectively. CYP3A has very broad substrate specificity, encompassing a wide variety of therapeutic agents.3) Many cancer chemotherapeutic agents such as vinca alkaloids, paclitaxel, irinotecan hydrochloride and other widely used drugs such as amiodarone, diltiazem, lovastatin, erythromycin, and midazolam are substrates for CYP3A. [4][5][6][7] Recently, individual variations in CYP3A activity in the human liver have been reported. 8)Because the pharmacokinetics of various drugs is influenced by individual variations in CYP3A activity, it is important to evaluate those variations in the clinical setting to achieve the optimum therapeutic outcomes. 9)Probe drugs including midazolam, erythromycin, nifedipine, lidocaine, and dextromethorphan and endogenous compounds such as cortisol and testosterone have been utilized to evaluate CYP3A activity.10,11) Watkins 12) proposed three specific CYP3A probes: erythromycin; midazolam; and cortisol. However, the probe drugs available for accurate, safe, and easy measurement of CYP3A activity remain limited.Lansoprazolebenzimidazole, is a proton-pump inhibitor (PPI) that suppresses gastric acid secretion by inhibiting (H ϩ /K ϩ )-ATPase and is prescribed commonly for the treatment of gastric ulcer, reflux esophagitis, etc., with few serious side effects reported. Following administration, lansoprazole is extensively metabolized to 5-hydroxylansoprazole and lansoprazole sulfone (LS) by CYP2C19 and CYP3A, respectively. 13) Masa et al. 14) reported that the metabolism to LS by CYP3A occurs independently of that to 5-hydroxylansoprazole by CYP2C19 in the human liver. Inhibition of one metabolic pathway caused by the genetic polymorphisms of CYPs leads to upregulation of another pathway in vivo. To use lansoprazole as probe drug, these problems should be elucidated in vitro or in vivo. The present study investigated the utility of lansoprazole in assessing CYP3A activity in comparison with previously reported in vitro methods. Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan: and b Research Laboratories, HAB Research Organization; 3rd Floor, Cornea Center Bldg., Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa, Chiba 272-8523, Japan. Received April 13, 2009; accepted May 15, 2009; published online June 1, 2009 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 det...

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Stereoselective Metabolism of Lansoprazole by Human Liver Cytochrome P450 Enzymes

Cited by 62 publications

References 19 publications

Lansoprazole Enantiomer Activates Human Liver Microsomal Cyp2c9 Catalytic Activity in a Stereospecific and Substrate-Specific Manner

Lansoprazole Enantiomer Activates Human Liver Microsomal Cyp2c9 Catalytic Activity in a Stereospecific and Substrate-Specific Manner

CYP2J2 and CYP2C19 Are the Major Enzymes Responsible for Metabolism of Albendazole and Fenbendazole in Human Liver Microsomes and Recombinant P450 Assay Systems

Potential of Lansoprazole as a Novel Probe for Cytochrome P450 3A Activity by Measuring Lansoprazole Sulfone in Human Liver Microsomes

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