Interaction of rs316019 variants of SLC22A2 with metformin and other drugs- an in silico analysis

Abstract

Metformin is one of the first-line and most widely prescribed drugs to treat type 2 diabetes (T2D). Its clearance from circulation is mostly facilitated by SLC22A2 (OCT2) in the renal cells. SLC22A2 is a polyspecific organic cation transporter and mediate transport of structurally unrelated endogenous and exogenous compounds including many drugs. rs316019 (p.270A > S) is the most common variant of SLC22A2 with a frequency as high as 15% or more in many populations. The 270S form of SLC22A2 clears metformin from circulation at much reduced level compared to the 270A form. If accumulated, metformin increases plasma lactate level in a concentration-dependent manner which can lead to a condition known as metformin-associated lactic acidosis (MALA). MALA is a potentially life-threatening complication with a mortality rate of 30–50%. Pre-existing clinical conditions, such as renal impairment, sepsis, anoxia, etc may make individuals more prone to MALA. In this study, we used computational approaches to investigate the effect of 270A > S change in SLC22A2 on interaction with metformin and other drugs. Based on the structural models, all substrates bind to the same pocket of SLC22A2. The substrates fit better to the binding site of 270A form of SLC22A2. The binding site has a few core interacting residues, among which SER358 appears to be the most important. It is an in silico prediction that the T2D patients, who are under metformin regimen, should be cautious in taking ranitidine (an over-the-counter sold drug) on a regular basis as it may lead to metformin associated lactate accumulation in blood.

Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine‐Drug Interactions

“…Many clinical creatinine‐drug interactions can be rationalized by inhibition of MATEs alone ( Figure ), and role of this transporter is supported by clinical genotyping studies ( Table ). Likewise, OCT2 genotype data support its role in creatinine renal disposition ( Table ), together with in silico structural modeling of creatinine interactions with variants of OCT2 37 . Conversely, confidence toward the in vivo role of OAT2 is limited by inconsistent in vitro uptake data from OAT2‐transfected cell lines, 38 limited genetic variability, and lack of drugs known or expected to inhibit OAT2 in vivo .…”

Genetic association of solute carrier transporter gene variants with metformin response

“…The rs316009 variant is located in a transcription factor binding motif and is in linkage disequilibrium with the non synonymous variant rs316019 [ 21 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. In previous studies, the TT genotype of rs316009 showed an increase response to metformin in comparison to the CC and CT genotypes [ 41 ].…”

“…From the data available, the CT genotype demonstrated a better response to treatment in comparison to the CC genotype ( Table 4 ). The rs316019 is the most common variant of SLC22A2 in many populations and has displayed contradictory results, linked to both decreased and increased renal clearance of metformin in healthy subjects [ 5 , 40 , 42 , 43 , 44 , 45 ].…”

The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

“…Through in silico analysis, Sajib et al found that substrates fit better to the binding site of the A270 variant as it is more open and has a wider space than the S270 variant [56]. The polymorphism rs316019 (A270S) is associated with reduced or no changes in transport activity.…”