Pharmacokinetic Differences between Lansoprazole Enantiomers and Contribution of Cytochrome P450 Isoforms to Enantioselective Metabolism of Lansoprazole in Dogs

The purpose of this study was to evaluate the pharmacokinetics of lansoprazole enantiomers and contribution of cytochrome P450 enzymes to enantioselective metabolism in dogs. The mean Cmax and area under the curve (AUC) values of (+)-lansoprazole were 4—5 times greater than those of (−)-lansoprazole...

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Published in:Biological & pharmaceutical bulletin 2001, Vol.24(3), pp.274-277
Main Authors: MASA, Kengo, HAMADA, Akinobu, ARIMORI, Kazuhiko, FUJII, Junko, NAKANO, Masahiro
Format: Article
Language:English
Subjects:
2-Pyridinylmethylsulfinylbenzimidazoles
Animals
Area Under Curve
Biological and medical sciences
Biotransformation
Cytochrome P-450 Enzyme System - metabolism
Digestive system
Dogs
Drug Interactions
enantiomer
enantioselectivity
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Half-Life
In Vitro Techniques
Isoenzymes - metabolism
Lansoprazole
Male
Medical sciences
metabolism
Microsomes, Liver - metabolism
Omeprazole - analogs & derivatives
Omeprazole - pharmacokinetics
Omeprazole - pharmacology
Pharmacology. Drug treatments
Protein Binding
Proton Pump Inhibitors
Stereoisomerism
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description The purpose of this study was to evaluate the pharmacokinetics of lansoprazole enantiomers and contribution of cytochrome P450 enzymes to enantioselective metabolism in dogs. The mean Cmax and area under the curve (AUC) values of (+)-lansoprazole were 4—5 times greater than those of (−)-lansoprazole following oral administration of 30-mg racemic lansoprazole to dogs. The CLtot/F values of (+)-lansoprazole were significantly smaller than those of (−)-lansoprazole (p
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The mean Cmax and area under the curve (AUC) values of (+)-lansoprazole were 4—5 times greater than those of (−)-lansoprazole following oral administration of 30-mg racemic lansoprazole to dogs. The CLtot/F values of (+)-lansoprazole were significantly smaller than those of (−)-lansoprazole (p&lt;0.05). The mean unbound fraction of (−)-lansoprazole was significantly greater than that of the (+)-lansoprazole. The amount of (+)-lansoprazole remaining was significantly greater than that of the (−)-lansoprazole after incubation of racemic lansoprazole in dog liver microsomes. When the effects of ticlopidine or ketoconazole on the metabolism of lansoprazole were studied using dog liver microsomes, ticlopidine significantly inhibited the formation of 5-hydroxylansoprazole, but not another metabolite, lansoprazole sulfone; however ketoconazole significantly inhibited formation of both metabolites. When the amount of (+)- and (−)-enantiomers remaining was measured in the presence and absence of ticlopidine, the amount of (+)-lansoprazole was significantly greater than that of the (−)-lansoprazole. On the other hand, there was no significant difference between the amount of (+)- and (−)-enantiomers remaining in combination with ketoconazole. These results suggest that the enantioselective pharmacokinetics of lansoprazole enantiomers are probably ascribable to their enantioselective protein binding and/or metabolism, and among the cytochrome P450 enzymes, CYP3A contributed to the enantioselective metabolism of lansoprazole.</description><identifier>ISSN: 0918-6158</identifier><identifier>EISSN: 1347-5215</identifier><identifier>DOI: 10.1248/bpb.24.274</identifier><identifier>PMID: 11256484</identifier><language>eng</language><publisher>Tokyo: The Pharmaceutical Society of Japan</publisher><subject>2-Pyridinylmethylsulfinylbenzimidazoles ; Animals ; Area Under Curve ; Biological and medical sciences ; Biotransformation ; Cytochrome P-450 Enzyme System - metabolism ; Digestive system ; Dogs ; Drug Interactions ; enantiomer ; enantioselectivity ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - pharmacology ; Half-Life ; In Vitro Techniques ; Isoenzymes - metabolism ; Lansoprazole ; Male ; Medical sciences ; metabolism ; Microsomes, Liver - metabolism ; Omeprazole - analogs &amp; derivatives ; Omeprazole - pharmacokinetics ; Omeprazole - pharmacology ; Pharmacology. 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The mean Cmax and area under the curve (AUC) values of (+)-lansoprazole were 4—5 times greater than those of (−)-lansoprazole following oral administration of 30-mg racemic lansoprazole to dogs. The CLtot/F values of (+)-lansoprazole were significantly smaller than those of (−)-lansoprazole (p&lt;0.05). The mean unbound fraction of (−)-lansoprazole was significantly greater than that of the (+)-lansoprazole. The amount of (+)-lansoprazole remaining was significantly greater than that of the (−)-lansoprazole after incubation of racemic lansoprazole in dog liver microsomes. When the effects of ticlopidine or ketoconazole on the metabolism of lansoprazole were studied using dog liver microsomes, ticlopidine significantly inhibited the formation of 5-hydroxylansoprazole, but not another metabolite, lansoprazole sulfone; however ketoconazole significantly inhibited formation of both metabolites. When the amount of (+)- and (−)-enantiomers remaining was measured in the presence and absence of ticlopidine, the amount of (+)-lansoprazole was significantly greater than that of the (−)-lansoprazole. On the other hand, there was no significant difference between the amount of (+)- and (−)-enantiomers remaining in combination with ketoconazole. These results suggest that the enantioselective pharmacokinetics of lansoprazole enantiomers are probably ascribable to their enantioselective protein binding and/or metabolism, and among the cytochrome P450 enzymes, CYP3A contributed to the enantioselective metabolism of lansoprazole.</description><subject>2-Pyridinylmethylsulfinylbenzimidazoles</subject><subject>Animals</subject><subject>Area Under Curve</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Digestive system</subject><subject>Dogs</subject><subject>Drug Interactions</subject><subject>enantiomer</subject><subject>enantioselectivity</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Half-Life</subject><subject>In Vitro Techniques</subject><subject>Isoenzymes - metabolism</subject><subject>Lansoprazole</subject><subject>Male</subject><subject>Medical sciences</subject><subject>metabolism</subject><subject>Microsomes, Liver - metabolism</subject><subject>Omeprazole - analogs &amp; derivatives</subject><subject>Omeprazole - pharmacokinetics</subject><subject>Omeprazole - pharmacology</subject><subject>Pharmacology. 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Drug treatments</topic><topic>Protein Binding</topic><topic>Proton Pump Inhibitors</topic><topic>Stereoisomerism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MASA, Kengo</creatorcontrib><creatorcontrib>HAMADA, Akinobu</creatorcontrib><creatorcontrib>ARIMORI, Kazuhiko</creatorcontrib><creatorcontrib>FUJII, Junko</creatorcontrib><creatorcontrib>NAKANO, Masahiro</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Biological &amp; pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MASA, Kengo</au><au>HAMADA, Akinobu</au><au>ARIMORI, Kazuhiko</au><au>FUJII, Junko</au><au>NAKANO, Masahiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacokinetic Differences between Lansoprazole Enantiomers and Contribution of Cytochrome P450 Isoforms to Enantioselective Metabolism of Lansoprazole in Dogs</atitle><jtitle>Biological &amp; pharmaceutical bulletin</jtitle><addtitle>Biol Pharm Bull</addtitle><date>2001-03-01</date><risdate>2001</risdate><volume>24</volume><issue>3</issue><spage>274</spage><epage>277</epage><pages>274-277</pages><issn>0918-6158</issn><eissn>1347-5215</eissn><abstract>The purpose of this study was to evaluate the pharmacokinetics of lansoprazole enantiomers and contribution of cytochrome P450 enzymes to enantioselective metabolism in dogs. The mean Cmax and area under the curve (AUC) values of (+)-lansoprazole were 4—5 times greater than those of (−)-lansoprazole following oral administration of 30-mg racemic lansoprazole to dogs. The CLtot/F values of (+)-lansoprazole were significantly smaller than those of (−)-lansoprazole (p&lt;0.05). The mean unbound fraction of (−)-lansoprazole was significantly greater than that of the (+)-lansoprazole. The amount of (+)-lansoprazole remaining was significantly greater than that of the (−)-lansoprazole after incubation of racemic lansoprazole in dog liver microsomes. When the effects of ticlopidine or ketoconazole on the metabolism of lansoprazole were studied using dog liver microsomes, ticlopidine significantly inhibited the formation of 5-hydroxylansoprazole, but not another metabolite, lansoprazole sulfone; however ketoconazole significantly inhibited formation of both metabolites. When the amount of (+)- and (−)-enantiomers remaining was measured in the presence and absence of ticlopidine, the amount of (+)-lansoprazole was significantly greater than that of the (−)-lansoprazole. On the other hand, there was no significant difference between the amount of (+)- and (−)-enantiomers remaining in combination with ketoconazole. These results suggest that the enantioselective pharmacokinetics of lansoprazole enantiomers are probably ascribable to their enantioselective protein binding and/or metabolism, and among the cytochrome P450 enzymes, CYP3A contributed to the enantioselective metabolism of lansoprazole.</abstract><cop>Tokyo</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>11256484</pmid><doi>10.1248/bpb.24.274</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record>
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subjects 2-Pyridinylmethylsulfinylbenzimidazoles
Animals
Area Under Curve
Biological and medical sciences
Biotransformation
Cytochrome P-450 Enzyme System - metabolism
Digestive system
Dogs
Drug Interactions
enantiomer
enantioselectivity
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Half-Life
In Vitro Techniques
Isoenzymes - metabolism
Lansoprazole
Male
Medical sciences
metabolism
Microsomes, Liver - metabolism
Omeprazole - analogs & derivatives
Omeprazole - pharmacokinetics
Omeprazole - pharmacology
Pharmacology. Drug treatments
Protein Binding
Proton Pump Inhibitors
Stereoisomerism
title Pharmacokinetic Differences between Lansoprazole Enantiomers and Contribution of Cytochrome P450 Isoforms to Enantioselective Metabolism of Lansoprazole in Dogs
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