title: Utilization of Liver Microsomes to Estimate Hepatic Intrinsic Clearance of Monoamine Oxidase Substrate Drugs in Humans.
abstract: Monoamine oxidases (MAOs) are non-CYP enzymes that contribute to systemic elimination of therapeutic agents, and localized on mitochondrial membranes. The aim of the present study was to validate quantitative estimation of metabolic clearance of MAO substrate drugs using human liver microsomes (HLMs).
  
  
  
  Three MAO substrate drugs, sumatriptan, rizatriptan and phenylephrine, as well as four CYP substrates were selected, and their disappearance during incubation with HLMs or mitochondria (HLMt) was measured. Metabolic clearance (CL) was then calculated from the disappearance curve.
  
  
  
  CL obtained in HLMs for sumatriptan and a typical MAO substrate serotonin was correlated with that obtained in HLMt among ten human individual livers. Hepatic intrinsic clearance (CLint,vitro) estimated from CL in HLMs was 14-20 and 2-5 times lower than in vivo hepatic intrinsic clearance (CLint,vivo) obtained from literature for MAO and CYP substrates, respectively. Utilization of HLMs for quantitatively assessing metabolic clearance of MAO substrates was further validated by proteomics approach which has revealed that numerous proteins localized on inner and outer membranes of mitochondria were detected in both HLMs and HLMt.
  
  
  
  CLint,vitrovalues of MAO substrate drugs can be quantitatively estimated with HLMs and could be used for semi-quantitative prediction of CLint,vivovalues.
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences,, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Masuo
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Shushi
authors.initials: S
authors.lastname: Nagamori
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences,, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
authors.forename: Aoi
authors.initials: A
authors.lastname: Hasegawa
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences,, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Isozumi
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences,, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Nakamichi
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences,, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. ykato@p.kanazawa-u.ac.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
mesh_terms: D006801:Humans; D007700:Kinetics; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000378:metabolism*; D010656:Phenylephrine / Q000378:metabolism* / Q000494:pharmacology; D018170:Sumatriptan / Q000378:metabolism* / Q000494:pharmacology; D014230:Triazoles / Q000378:metabolism* / Q000494:pharmacology; D014363:Tryptamines / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D014230:Triazoles; D014363:Tryptamines; D010656:Phenylephrine; C093622:rizatriptan; D018170:Sumatriptan; D008995:Monoamine Oxidase
keywords: Drug metabolism; Hepatic clearance; In vitro-in vivo extrapolation; Monoamine oxidase