Renal Drug Transporters and Drug Interactions

Abstract

Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.

Clinical pharmacokinetics of oral drugs in the treatment of multiple myeloma

“…Consistent with previous in vitro findings, a clinical DDI study performed in healthy subjects with a substrate (i.e., digoxin) and an inhibitor of P‐gp (i.e., quinidine) showed that these drugs did not influence lenalidomide plasma levels (and vice versa) . Moreover, DDIs involving transporters at the renal level are usually of limited magnitude as shown recently in a comprehensive review . The DDI interaction observed in patients (between temsirolimus and lenalidomide) may arise from the fact that the role of P‐gp in MM patients might be altered by changes induced by the disease in the proximal tubules leading to clinically significant DDIs …”

Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2)

“…Increasing evidence has indicated that a drug transporter can be a site of significant DDIs where a ‘perpetrator’ drug can affect the clearance and the systemic exposure of a ‘victim’ drug, resulting in exaggerated/diminished therapeutic and/or side effects (39). Morphine is commonly co-administrated with other drugs which may serve as “perpetrator” agents via transporter inhibition and cause undesirable outcomes of morphine.…”

Impact of Viral Inflammation on the Expression of Renal Drug Transporters in Pregnant Rats

“…Membrane protein fractions were extracted from tissues as previously described (23). Briefly, renal tissue (300 mg) was homogenized in lysis buffer (0.1 M Tris-HCL (Sigma Aldrich), pH 7.5), containing 3 µL/mL protease inhibitor cocktail (Sigma Aldrich), and 50 µg/mL phenylmethylsulfonyl fluoride (Bioshop, Burlington, ON, Canada).…”