Overview of the OATP family

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Overview of the OATP family

• Andy Ayrton

Annual Meeting Baltimore, MD November 7-11, 2004
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Relevance of drug transporters

• Knowledge on localization and function support an
  understanding of
• The mechanisms of drug AD(M)E
• Drug targeting and delivery
• Certain mechanisms of drug toxicity
• Allows assessment of risk and prediction of
• AD(M)ET
• Drug-drug and drug-food interaction liability

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OATP Phylogenetic Tree
gt 40 a.a. identity
gt 60 a.a. identity
Hagenbuch and Meier (2004)Pflugers Arch Eur J
Physiol 447, 663-665
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Members of the hOATP Family
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Structure
Predicted Transmembrane Domain Model of rOatp1
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Distribution
Human
Rat
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Distribution
Human
Rat
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Distribution
Human
Rat
?
?
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Function
Na-independent exchange transporters
Substrate
HC03-, glutathione, GS-conjugates

• Substrates tend to be amphipathic molecules with
  high molecular weight (gt450)

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Function
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Impact Disposition of an OA
Low Vd Moderate CL LiverMuscle 1001 90
eliminated unchanged in Bile
Saturable human hepatic uptake
Non-linear PK (human)
Passive
Active
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Inhibition
Probe Estradiol glucuronide Test System CHO
OATP1B1 cells
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Impact Disposition Of Rosuvastatin
Limited F
Cyclosporine
Hepatic portal vein
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Summary

• Key mechanisms in the absorption, distribution
  and elimination of many drugs
• Saturable process that can give rise to
  non-linear PK
• Inhibition can result in
• significant drug-drug
• alteration of normal physiological processes