Skip to main content

Advertisement

SpringerLink
Log in

Utilization of Liver Microsomes to Estimate Hepatic Intrinsic Clearance of Monoamine Oxidase Substrate Drugs in Humans

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

CL:

In vitro metabolic clearance

CLint :

Intrinsic clearance

CYP:

Cytochrome P450

HLMs:

Human liver microsomes

HLMt:

Human liver mitochondria

IVIVE:

In vitro-in vivo extrapolation

LC-MS/MS:

Liquid chromatography-mass spectrometry/mass spectrometry

MAO:

Monoamine oxidase

NADPH:

Nicotinamide adenine dinucleotide phosphate

References

  1. Chiba M, Ishii Y, Sugiyama Y. Prediction of hepatic clearance in human from in vitro data for successful drug development. AAPS J. 2009;11(2):262–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pryde DC, Dalvie D, Hu Q, Jones P, Obach RS, Tran TD. Aldehyde oxidase: an enzyme of emerging importance in drug discovery. J Med Chem. 2010;53(24):8441–60.

    Article  CAS  PubMed  Google Scholar 

  3. Brandon EF, Raap CD, Meijerman I, Beijnen JH, Schellens JH. An update on in vitro test methods in human hepatic drug biotransformation research: pros and cons. Toxicol Appl Pharmacol. 2003;189(3):233–46.

    Article  CAS  PubMed  Google Scholar 

  4. Kilford PJ, Stringer R, Sohal B, Houston JB, Galetin A. Prediction of drug clearance by glucuronidation from in vitro data: use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes. Drug Metab Dispos. 2009;37(1):82–9.

    Article  CAS  PubMed  Google Scholar 

  5. Miners JO, Knights KM, Houston JB, Mackenzie PI. In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: pitfalls and promises. Biochem Pharmacol. 2006;71(11):1531–9.

    Article  CAS  PubMed  Google Scholar 

  6. Akabane T, Gerst N, Masters JN, Tamura K. A quantitative approach to hepatic clearance prediction of metabolism by aldehyde oxidase using custom pooled hepatocytes. Xenobiotica. 2012;42(9):863–71.

    Article  CAS  PubMed  Google Scholar 

  7. Strolin Benedetti M, Whomsley R, Baltes E. Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics. Expert Opin Drug Metab Toxicol. 2006;2(6):895–921.

    Article  CAS  PubMed  Google Scholar 

  8. Berry MD, Juorio AV, Paterson IA. The functional role of monoamine oxidases a and B in the mammalian central nervous system. Prog Neurobiol. 1994;42(3):375–91.

    Article  CAS  PubMed  Google Scholar 

  9. Saura J, Nadal E, van den Berg B, Vila M, Bombi JA, Mahy N. Localization of monoamine oxidases in human peripheral tissues. Life Sci. 1996;59(16):1341–9.

    Article  CAS  PubMed  Google Scholar 

  10. Shih JC, Chen K, Ridd MJ. Monoamine oxidase: from genes to behavior. Annu Rev Neurosci. 1999;22:197–217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kamel A, Colizza K, Gunduz M, Harriman S, Obach RS. In vitro-in vivo correlation for intrinsic clearance for CP-409,092 and sumatriptan: a case study to predict the in vivo clearance for compounds metabolized by monoamine oxidase. Xenobiotica. 2012;42(4):355–62.

    Article  CAS  PubMed  Google Scholar 

  12. Dixon CM, Park GR, Tarbit MH. Characterization of the enzyme responsible for the metabolism of sumatriptan in human liver. Biochem Pharmacol. 1994;47(7):1253–7.

    Article  CAS  PubMed  Google Scholar 

  13. Iwasa T, Sano H, Sugiura A, Uchiyama N, Hara K, Okochi H, et al. An in vitro interethnic comparison of monoamine oxidase activities between Japanese and Caucasian livers using rizatriptan, a serotonin receptor 1B/1D agonist, as a model drug. Br J Clin Pharmacol. 2003;56(5):537–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yu AM, Granvil CP, Haining RL, Krausz KW, Corchero J, Kupfer A, et al. The relative contribution of monoamine oxidase and cytochrome p450 isozymes to the metabolic deamination of the trace amine tryptamine. J Pharmacol Exp Ther. 2003;304(2):539–46.

    Article  CAS  PubMed  Google Scholar 

  15. Zientek M, Jiang Y, Youdim K, Obach RS. In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase. Drug Metab Dispos. 2010;38(8):1322–7.

    Article  CAS  PubMed  Google Scholar 

  16. Ito K, Houston JB. Prediction of human drug clearance from in vitro and preclinical data using physiologically based and empirical approaches. Pharm Res. 2005;22(1):103–12.

    Article  CAS  PubMed  Google Scholar 

  17. Ciraulo DA, Barnhill JG, Jaffe JH. Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers. Clin Pharmacol Ther. 1988;43(5):509–18.

    Article  CAS  PubMed  Google Scholar 

  18. Dixon CM, Saynor DA, Andrew PD, Oxford J, Bradbury A, Tarbit MH. Disposition of sumatriptan in laboratory animals and humans. Drug Metab Dispos. 1993;21(5):761–9.

    CAS  PubMed  Google Scholar 

  19. Vyas KP, Halpin RA, Geer LA, Ellis JD, Liu L, Cheng H, et al. Disposition and pharmacokinetics of the antimigraine drug, rizatriptan, in humans. Drug Metab Dispos. 2000;28(1):89–95.

    CAS  PubMed  Google Scholar 

  20. Milton KA, Scott NR, Allen MJ, Abel S, Jenkins VC, James GC, et al. Pharmacokinetics, pharmacodynamics, and safety of the 5-HT(1B/1D) agonist eletriptan following intravenous and oral administration. J Clin Pharmacol. 2002;42(5):528–39.

    Article  CAS  PubMed  Google Scholar 

  21. Sogaard B, Mengel H, Rao N, Larsen F. The pharmacokinetics of escitalopram after oral and intravenous administration of single and multiple doses to healthy subjects. J Clin Pharmacol. 2005;45(12):1400–6.

    Article  CAS  PubMed  Google Scholar 

  22. Sandrini G, Perrotta A, Tassorelli C, Nappi G. Eletriptan. Expert Opin Drug Metab Toxicol. 2009;5(12):1587–98.

    Article  CAS  PubMed  Google Scholar 

  23. Mandrioli R, Mercolini L, Raggi MA. Evaluation of the pharmacokinetics, safety and clinical efficacy of sertraline used to treat social anxiety. Expert Opin Drug Metab Toxicol. 2013;9(11):1495–505.

    Article  CAS  PubMed  Google Scholar 

  24. Tfelt-Hansen P, Hougaard A. Sumatriptan: a review of its pharmacokinetics, pharmacodynamics and efficacy in the acute treatment of migraine. Expert Opin Drug Metab Toxicol. 2013;9(1):91–103.

    Article  CAS  PubMed  Google Scholar 

  25. Janin A, Monnet J. Bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a fixed-combination syrup versus an oral reference product. The Journal of International Medical Research. 2014;42(2):347–59.

    Article  PubMed  Google Scholar 

  26. Iwatsubo T, Hirota N, Ooie T, Suzuki H, Sugiyama Y. Prediction of in vivo drug disposition from in vitro data based on physiological pharmacokinetics. Biopharm Drug Dispos. 1996;17(4):273–310.

    Article  CAS  PubMed  Google Scholar 

  27. Uetsuka S, Ogata G, Nagamori S, Isozumi N, Nin F, Yoshida T, et al. Molecular architecture of the stria vascularis membrane transport system, which is essential for physiological functions of the mammalian cochlea. Eur J Neurosci. 2015;42(3):1984–2002.

    Article  PubMed  Google Scholar 

  28. Masuda T, Tomita M, Ishihama Y. Phase transfer surfactant-aided trypsin digestion for membrane proteome analysis. J Proteome Res. 2008;7(2):731–40.

    Article  CAS  PubMed  Google Scholar 

  29. Rappsilber J, Mann M, Ishihama Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc. 2007;2(8):1896–906.

    Article  CAS  PubMed  Google Scholar 

  30. Silva JC, Gorenstein MV, Li GZ, Vissers JP, Geromanos SJ. Absolute quantification of proteins by LCMSE: a virtue of parallel MS acquisition. Mol Cell Proteomics. 2006;5(1):144–56.

    Article  CAS  PubMed  Google Scholar 

  31. Ferrari A, Sternieri E, Ferraris E, Bertolini A. Emerging problems in the pharmacology of migraine: interactions between triptans and drugs for prophylaxis. Pharmacol Res. 2003;48(1):1–9.

    CAS  PubMed  Google Scholar 

  32. Evans DC, O'Connor D, Lake BG, Evers R, Allen C, Hargreaves R. Eletriptan metabolism by human hepatic CYP450 enzymes and transport by human P-glycoprotein. Drug Metab Dispos. 2003;31(7):861–9.

    Article  CAS  PubMed  Google Scholar 

  33. Ji Y, Schaid DJ, Desta Z, Kubo M, Batzler AJ, Snyder K, et al. Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations. Br J Clin Pharmacol. 2014;78(2):373–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kobayashi K, Ishizuka T, Shimada N, Yoshimura Y, Kamijima K, Chiba K. Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug Metab Dispos. 1999;27(7):763–6.

    CAS  PubMed  Google Scholar 

  35. Di Consiglio E, Meneguz A, Testai E. Organophosphorothionate pesticides inhibit the bioactivation of imipramine by human hepatic cytochrome P450s. Toxicol Appl Pharmacol. 2005;205(3):237–46.

    Article  CAS  PubMed  Google Scholar 

  36. Nakamori F, Naritomi Y, Furutani M, Takamura F, Miura H, Murai H, et al. Correlation of intrinsic in vitro and in vivo clearance for drugs metabolized by hepatic UDP-glucuronosyltransferases in rats. Drug Metabolism and Pharmacokinetics. 2011;26(5):465–73.

    Article  CAS  PubMed  Google Scholar 

  37. Boxenbaum H. Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: extrapolation of data to benzodiazepines and phenytoin. J Pharmacokinet Biopharm. 1980;8(2):165–76.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences,, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan

    Yusuke Masuo, Aoi Hasegawa, Kazuki Hayashi, Noritaka Nakamichi & Yukio Kato

  2. Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Shushi Nagamori, Noriyoshi Isozumi & Yoshikatsu Kanai

Authors
  1. Yusuke Masuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shushi Nagamori
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aoi Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuki Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Noriyoshi Isozumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Noritaka Nakamichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshikatsu Kanai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yukio Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yukio Kato.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Masuo, Y., Nagamori, S., Hasegawa, A. et al. Utilization of Liver Microsomes to Estimate Hepatic Intrinsic Clearance of Monoamine Oxidase Substrate Drugs in Humans. Pharm Res 34, 1233–1243 (2017). https://doi.org/10.1007/s11095-017-2140-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-017-2140-4

Key Words

Search

Navigation