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.

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Presentation transcript:

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 25.10.2017

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 25.10.2017

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 25.10.2017

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 25.10.2017

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 25.10.2017

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 25.10.2017

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 25.10.2017

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 25.10.2017

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 25.10.2017