Transporter-Mediated Drug–Drug Interactions with Oral Antidiabetic Drugs

Sabine Klatt,Jörg König,Martin F Fromm

doi:10.3390/pharmaceutics3040680

Sabine Klatt, Jörg König + Show 1 more

Open Access

https://doi.org/10.3390/pharmaceutics3040680

Copy DOI

Journal: Pharmaceutics	Publication Date: Oct 12, 2011
Citations: 141	License type: CC BY 3.0

Affiliation: University of Erlangen-Nuremberg

Abstract

Uptake transporters (e.g., members of the SLC superfamily of solute carriers) and export proteins (e.g., members of the ABC transporter superfamily) are important determinants for the pharmacokinetics of drugs. Alterations of drug transport due to concomitantly administered drugs that interfere with drug transport may alter the kinetics of drug substrates. In vitro and in vivo studies indicate that many drugs used for the treatment of metabolic disorders and cardiovascular diseases (e.g., oral antidiabetic drugs, statins) are substrates for uptake transporters and export proteins expressed in the intestine, the liver and the kidney. Since most patients with type 2 diabetes receive more than one drug, transporter-mediated drug-drug interactions are important molecular mechanisms leading to alterations in oral antidiabetic drug pharmacokinetics with the risk of adverse drug reactions. This review focuses on uptake transporters of the SLCO/SLC21 (OATP) and SLC22 (OCT/OAT) family of solute carriers and export pumps of the ABC (ATP-binding cassette) transporter superfamily (especially P-glycoprotein) as well as the export proteins of the SLC47 (MATE) family and their role for transporter-mediated drug-drug interactions with oral antidiabetic drugs.

Highlights

Drug effects result from the interplay of multiple processes that influence drug absorption, metabolism and excretion as well as drug response
This review describes oral antidiabetic drugs and transportermediated drug-drug interactions and we especially focus on the uptake transporters OATP1B1, OATP1B3 (SLCO1B3) and OATP2B1 (SLCO2B1) of the SLC21/SLCO family, the SLC22 family members OCT1 (SLC22A1), OCT2 (SLC22A2) and OCT3 (SLC22A3) and the sodium-dependent bile salt transporter NTCP belonging to the SLC10 family
These analyses revealed that Organic anion transporting polypeptides (OATPs) are important molecular targets of transporter-mediated drug-drug interactions since their substrate spectrum includes a variety of frequently prescribed drugs often administered concomitantly with oral antidiabetic drugs

Summary

Introduction

Drug effects result from the interplay of multiple processes that influence drug absorption, metabolism and excretion as well as drug response. This review describes oral antidiabetic drugs and transportermediated drug-drug interactions and we especially focus on the uptake transporters OATP1B1 (gene symbol: SLCO1B1), OATP1B3 (SLCO1B3) and OATP2B1 (SLCO2B1) of the SLC21/SLCO family, the SLC22 family members OCT1 (SLC22A1), OCT2 (SLC22A2) and OCT3 (SLC22A3) and the sodium-dependent bile salt transporter NTCP belonging to the SLC10 family. Whereas human MATE1 is strongly expressed in liver and kidney (Figure 1) and to a lesser extent in several other tissues including skeletal muscle and testis [44,45], MATE2 is almost exclusively expressed in the kidney and localized in the luminal membrane of proximal tubular epithelial cells. The characteristics of some widely used oral antidiabetic drugs together with their mode of action, metabolizing enzymes and transport proteins relevant for their membrane translocation or drug-drug interactions are summarized in Table. Activation of AMP-activated protein kinase (AMPK) and suppression of glucagonstimulated glucose production, increase in glucose uptake in muscle and hepatic cells

Oral Antidiabetic Drugs and OATPs

Oral Antidiabetic Drugs and OCTs

Findings

Oral Antidiabetic Drugs and Export Proteins