Figure 11 Distribution of the main drug ABC (blue) and SLC (red) transporters on the basolateral (peritubular fluid) and apical (glomerular filtrate) membranes of the kidney proximal tubule cells.

methotrexate.148 OCs are similarly transported by OCT 1, OCT2, and OCT3; the efflux transporters MRP1, MRP3, MRP5, and MRP6 mediate their efflux back into the systemic circulation.114,134 The sulfate-anion antiporter 1 (SAT-1; SLC26A1) is responsible for the sodium-dependent movement of sulfate across the basolateral membrane of the proximal tubule in exchange for HCO3—, but organic anions can also be substrates or inhibitors of SAT-1.98 At the apical membrane, OAT4 and URAT1, OCTN1, and OCTN2 can mediate drug transport with bidirectional properties, either secretion or reabsorption. For example, OCTN2 secretes OCs and reabsorbs zwitterions. OATP1A2, PEPT1, and PEPT2 mediate the reabsorption of their substrates from the tubule lumen (see Section

The ABC transporters MDR1, MRP2, and MRP4 are also present on the apical membrane and efflux compounds by secretion. As indicated above, transporters are not evenly distributed along the nephron: MDR1, MRP2, MRP4, and MRP6 are found mainly within the three segments of the proximal tubule; MRP3 lies in the distal convoluted tubule; and MRP1 is found in the epithelial cells of the loop of Henle and the distal and collecting duct tubule cells, but not in proximal tubule cells.114 The regional distributions of the SLC transporters are also specific. OAT1 is found only on the basolateral membrane of the S2 segment cells of the proximal tubule, whereas OAT3 is present on the cells of the S1, S2, and S3 segments. Once again, this raises the question of the most appropriate in vitro kidney models containing the whole transport network. As with Caco-2 intestinal cells, the Madin-Darby canine kidney (MDCK) cell lines are widely used in wild-type or transfected cell systems for examining particular transport processes.149,150 They are useful in vitro tools for assessing the risks of drug-drug interactions, nephrotoxicity, and drug efficacy mediated by the reabsorptive and secretory capacities of the kidney.

If the renal clearance of a drug is equal to or more than the overall body clearance, renal transporters can be important in clinical efficacy or toxicity. For example, the cephalosporin antibiotics are primary eliminated via the kidney. Creatinine clearance is normally 100-140 mLmin — 1, but the renal clearance of cephalosporins is 16.8-469 mLmin— 1, suggesting that some of them, like cefotaxine and cefadroxil, are excreted into the urine by tubular secretion, whereas others, like ceftriaxone and cefazodin, the renal clearance of which is less than that of creatinine, are reabsorbed.151

OAT1, OAT2, and OAT3 are located on the basolateral side of the proximal tubule and mediate the uptake of most of the cephalosporins into the proximal tubule from the peritubular capillary. The apical OAT4 mediates both the uptake (reabsorption from the tubular lumen) and the efflux (secretion) of these anionic antibiotics.95 Like the basolateral transporters of hepatocytes, which can modulate the pharmacological activity of drugs acting via intrahepatocyte targets or induce hepatotoxicity, the basolateral OATs can make some cephalosporins cause nephrotoxicity, which may lead to acute proximal tubular necrosis. This toxicity is mainly due to the accumulation of cephalosporin in the renal cortex because of the lack of efficient vectorial transtubular transport.95,98,152 This transportmediated nephrotoxicity also results in the adverse effect of cisplastin drugs via their basolateral uptake in the proximal tubule by OCT2 and the toxic effects depend on the platinum complex used, as does the structure-dependent nephrotoxicity of cephalosporins.153 Nephrotoxicity also limits the use of the nucleoside phosphonates, adefovir and cidofovir, in the treatment of human immunodeficiency virus. The toxicity of these drugs appears to be a function of both OAT1-mediated proximal tubular accumulation and decreased efflux at the luminal membrane by MRP2. A small dose of the OAT1 inhibitor, probenecid, may reduce the nephrotoxicity of cidofovir.154

The use of transporter inhibitors to reduce nephrotoxicity suggests that drug-drug interactions affecting anionic and cationic drugs can be mediated via competition at the basolateral and luminal tubular transporters. Multiple drug-drug interactions have been reported with probenecid and cimetidine, and there have been fatal cases with methotrexate and NSAIDs following the inhibition of the basolateral OAT1 and OAT3.155

Finally, renal transporters can be critical for the action of diuretics. Tubular secretion is the main route by which diuretics act in the kidney and are excreted. The diuretic drugs, such as the thiazides, the loop diuretics bumetanide and furosemide, and the carbonic anhydrase inhibitors, are all competitive inhibitors of the renal OATs, although their affinities and specificities vary.156 Transporters and the Biopharmaceutics Classification System

Amidon et al.157 have devised a biopharmaceutics classification system (BCS) that divides drugs into four classes according to their solubility and permeability (see 5.42 The Biopharmaceutics Classification System). The BCS has produced rates and extents by which oral drugs are absorbed. Extended versions of the BCS have been proposed by associating the four classes with the main routes of elimination and the effects of efflux and influx transporters. Their objectives were to predict the pharmacokinetic performance of a drug product in vivo from measurements of permeability and solubility. Figure 12 combines the first elements of the original BCS and additional information on the main pathways of drug elimination and the impact of drug transporters.158 Most class 1 and class 2 compounds, which are highly permeable, are eliminated via metabolism, whereas class 3 and 4 compounds, which are poorly permeable, are primarily eliminated unchanged into the urine and/or bile. The effect of intestinal transporters is expected to be minimal for class 1 compounds, even if they interact with transporters, as their great permeability and solubility allows high concentrations in the gut lumen to saturate any transporter. In contrast, many large (>500 Da), lipophilic and poorly water-soluble new BCS class 2 molecules that deviate the crude Lipinski filter rule of 5 are often the target of gut efflux transporters such as MDR1 and BCRP.158 Sufficient amounts of class 3 drugs will be available for gut absorption because of their great solubility, but their poor permeability requires an absorptive transporter. The poor oral bioavailability and transporter effects are likely to determine the oral absorption of class 4 compounds.

The postabsorptive pharmacokinetics can also be anticipated with the BCS. Most of the drugs with high hepatic extraction ratios and clearances approaching the hepatic blood flow are class 1 compounds, and the target mediating drug-drug interactions is primarily metabolic. In contrast, both uptake and efflux transporters are critical determinants of the disposition of class 2, 3, and 4 compounds, the biliary secretion and renal secretion or reabsorption-mediated transport of which can dramatically modulate the systemic concentrations of these drugs. Thus, transporters may be the primary mediators of drug-drug interactions.

High solubility Low solubility

High permeability

Class 1 (high solubility, high permeability)

Metabolism 'High hepatic extraction'

Class 2 (low solubility, high permeability)


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