TY - JOUR
T1 - Utilization of Liver Microsomes to Estimate Hepatic Intrinsic Clearance of Monoamine Oxidase Substrate Drugs in Humans
AU - Masuo, Yusuke
AU - Nagamori, Shushi
AU - Hasegawa, Aoi
AU - Hayashi, Kazuki
AU - Isozumi, Noriyoshi
AU - Nakamichi, Noritaka
AU - Kanai, Yoshikatsu
AU - Kato, Yukio
N1 - Publisher Copyright:
© 2017, Springer Science+Business Media New York.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Purpose: 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). Methods: 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. Results: 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. Conclusion: CLint,vitro values of MAO substrate drugs can be quantitatively estimated with HLMs and could be used for semi-quantitative prediction of CLint,vivo values.
AB - Purpose: 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). Methods: 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. Results: 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. Conclusion: CLint,vitro values of MAO substrate drugs can be quantitatively estimated with HLMs and could be used for semi-quantitative prediction of CLint,vivo values.
KW - Drug metabolism
KW - Hepatic clearance
KW - In vitro-in vivo extrapolation
KW - Monoamine oxidase
UR - https://www.scopus.com/pages/publications/85016477856
UR - https://www.scopus.com/pages/publications/85016477856#tab=citedBy
U2 - 10.1007/s11095-017-2140-4
DO - 10.1007/s11095-017-2140-4
M3 - Article
C2 - 28361200
AN - SCOPUS:85016477856
SN - 0724-8741
VL - 34
SP - 1233
EP - 1243
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 6
ER -