1. Recent advance in the pharmacogenomics of human Solute Carrier Transporters (SLCs) in drug disposition
Zhou F, Zhub L, Wang K, Murray M
Advanced Drug Delivery Reviews 116, 21–36
2017
Heli Parviainen, Helsinki

2. Heli Parviainen, Helsinki 25.10.2017
Objectives
A quick overview on the most well known Solute Carrier Transporters (SLCs)
Discussion on the effects of different transporter genotypes and fenotypes on pharmacokinetic profiles of drugs
Possible view points for further researchs
Heli Parviainen, Helsinki

3. Solute Carrier Transporters, SLCs
Influx transporters that are responsible for the cellular uptake of several drug molecules
SLC superfamily has more than 300 members
Expressed in many types of tissues
Chemically diverse substrates: cations, anions, and neutral or zwitterionic compounds
Responsible for maintaining homeostasis in the body
Heli Parviainen, Helsinki

4. Organic Anion Transporting Polypeptides, OATPs
Multispecific transporters, broadest substrate spectrum among SLCs
Most of the substrates are large hydrophobic anions
Isomembers in the transporter family share common substrates
Transporters are widely expressed in the body, especially in the liver, kidneys and intestine
Heli Parviainen, Helsinki

5. Examples of notable OATP isomembers
OATP1B1
Has the most pharmacogenomic data available
Expression level has been shown to have a significant impact on the pharmacokinetics of many statin drugs
OATP1A2
Substrates include imatinib, fexofenadine, methotrexate and HIV protease inhibitors
Genetic polymorphism may have an impact on the CNS entry of methotrexate and opioid peptides
Heli Parviainen, Helsinki

6. Organic anion transporters, OATs
Most OATs are expressed in the kidney or liver
Known for regulating active secretion and uptake of many molecules in tubular cells
Have a broad spectrum of substrates, for example anti-cancer drugs, antibiotics and anti-hypertensives
Some subtypes can also transport cations
Heli Parviainen, Helsinki

7. Organic cation transporters, OCTs/OCTNs
Coded by the samegene population as OATs
Termed polyspecific
Responsible for transport of substrates with large variation in molecular structures and sizes
OCT1 has been shown to have a significant impact on metformin and morphine pharmacokinetics
OCT2 has been shown to transport substrates in bi-directional manner
Heli Parviainen, Helsinki

8. The impact of SLCs in pharmacokinetics
The ADME parameters of a drug are determined by drug metabolizing enzymes and transporters
As transporters the SLCs mediate the distribution of drugs
Genetic variation in SLC coding regions can change the pharmacokinetics of a drug via
Mutations affecting the activity of a transporter
Mutations affecting the expression of a transporter
Heli Parviainen, Helsinki

9. Impact on pharmaceutical research
Current focus
Transporter polymorphism association with drug pharmacokinetics
Molecular forms of genetic variants in context of specific substrate uptake
Possible future studies
Correlation between phenotype and genotype
Integrating in vitro experimental results to human studies
Heli Parviainen, Helsinki