Kidney Transplantation Down-Regulates Expression of Organic Cation Transporters, Which Translocate β-Blockers and Fluoroquinolones

Abstract

Kidney transplanted patients are often treated with immunosuppressive, antihypertensive, and antibiotic drugs such as cyclosporine A (CsA), β-blockers, and fluoroquinolones, respectively. Organic cation transporters (OCT) expressed in the basolateral membrane of proximal tubules represent an important drug excretion route. In this work, the renal expression of OCT after syngeneic and allogeneic kidney transplantation in rats with or without CsA immunosuppression was studied. Moreover, the interactions of CsA, β-blockers (pindolol/atenolol), and fluoroquinolones (ofloxacin/norfloxacin) with rOCT1, rOCT2, hOCT1, and hOCT2 in stably transfected HEK293-cells were studied. Kidney transplantation was associated with reduced expression of rOCT1, while rOCT2 showed only reduced expression after allogeneic transplantation. All drugs interacted subtype- and species-dependently with OCT. However, only atenolol, pindolol, and ofloxacin were transported by hOCT2, the main OCT in human kidneys. While CsA is not an OCT substrate, it exerts a short-term effect on OCT activity, changing their affinity for some substrates. In conclusion, appropriate drug dosing in transplanted patients is difficult partly because OCT are down-regulated and because concomitant CsA treatment may influence the affinity of the transporters. Moreover, drug-drug competition at the transporter can also alter drug excretion rate.

Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

“…In contrast to a previous study that indicated no transport of atenolol by hOCT1 (Ciarimboli et al, 2013), our data clearly demonstrated that atenolol is an excellent substrate of hOCT1 ( Figs. 2 and 3; Tables 1 and 2).…”

“…Recently, Ciarimboli et al showed that hOCTs interact with several b-blockers and may also accept some b-blockers as substrates (Ciarimboli et al, 2013). Based on the physiochemical property of atenolol and the known renal elimination mechanism of organ cations, we hypothesized that renal secretion of atenolol is mediated by the hOCT2/hMATEs pathway.…”

Revisiting atenolol as a low passive permeability marker

“…However, another study by Mimura et al suggested that organic cation transporter 1 (OCT1) rather than OATP probably contributes to the interaction between atenolol and flavonoids in fruit juices [ 47 ]. It was also reported that hOCT2 at the basolateral membrane of kidney tubules lead to renal active secretion of atenolol [ 48 ]. Furthermore, the study performed by Yin et al suggested that atenolol is also a substrate of multidrug and toxin extrusion proteins (hMATE-1 and hMATE2-K) located at the apical membrane of renal tubule, thus contributing to the elimination of atenolol from blood to urine together with OCT2 [ 49 ].…”

Role of the Plasma Membrane Transporter of Organic Cations OCT1 and Its Genetic Variants in Modern Liver Pharmacology

“…Similarly, OCT1 plays a key role in the first-pass effect through the liver and hence in the bioavailability of other cationic drugs, such as amantadine, levodopa and pramipexole [40], cimetidine [91], ciprofloxacin and other fluoroquinolones [92, 93], furamidine and pentamidine [100], lamotrigine [89], sulpiride [90], and zalcitabine [101]. …”

“…In the case of treatments based on cationic antineoplastic drugs, the combined treatment may reduce the uptake of these drugs by the tumor and hence decrease the efficacy of the chemotherapy [43]. Additional examples for such a clinically relevant interaction include antibiotics and antihypertensives [92]. …”