Cellular and molecular aspects of drug transport in the kidney

Cellular and molecular aspects of drug transport in the kidney. The kidney plays an important role in the elimination of numerous hydrophilic xenobiotics, including drugs, toxins, and endogenous compounds. It has developed high-capacity transport systems to prevent urinary loss of filtered nutrients, as well as electrolytes, and simultaneously to facilitate tubular secretion of a wide range of organic ions. Transport systems for organic anions and cations are primarily involved in the secretion of drugs in renal tubules. The identification and characterization of organic anion and cation transporters have been progressing at the molecular level. To date, many members of the organic anion transporter (OAT), organic cation transporter (OCT), and organic anion-transporting polypeptide (oatp) gene families have been found to mediate the transport of diverse organic anions and cations. It has also been suggested that ATP-dependent primary active transporters such as MDR1/P-glycoprotein and the multidrug resistance-associated protein (MRP) gene family function as efflux pumps of renal tubular cells for more hydrophobic molecules and anionic conjugates. Tubular reabsorption of peptide-like drugs such as β-lactam antibiotics across the brush-border membranes appears to be mediated by two distinct H+/peptide cotransporters: PEPT1 and PEPT2. Renal disposition of drugs is the consequence of interaction and/or transport via these diverse secretory and absorptive transporters in renal tubules. Studies of the functional characteristics, such as substrate specificity and transport mechanisms, and of the localization of cloned drug transporters could provide information regarding the cellular network involved in renal handling of drugs. Detailed information concerning molecular and cellular aspects of drug transporters expressed in the kidney has facilitated studies of the mechanisms underlying renal disposition as well as transporter-mediated drug interactions

Cyp3a5 genotype as a potential pharmacodynamic biomarker for tacrolimus therapy in ulcerative colitis in japanese patients

Tacrolimus has been used to induce remission in patients with steroid-refractory ulcerative colitis. It poses a problem of large individual differences in dosage necessary to attain target blood concentration and, often, this leads to drug inefficacy. We examined the difference in mRNA expression levels of ATP binding cassette transporter B1 (ABCB1) between inflamed and non-inflamed tissues, and the influence of CYP3A5 genotype on tacrolimus therapy. The mRNA expression of CYP3A4 in colonic mucosa and that of cytochrome p450 3A5 (CYP3A5) and ABCB1 in inflamed and non-inflamed areas were examined in 14 subjects. The mRNA expression levels of CYP3A5 were higher than that of CYP3A4. The mRNA expression of ABCB1 was lower in the inflamed than in the non-inflamed mucosa, despite that of CYP3A5 mRNA level being not significantly changed. Hence, the deterioration of the disease is related to the reduction of the barrier in the inflamed mucosa. The relationship between CYP3A5 genotype and blood concentration, dose, and concentration/dose (C/D) ratio of tacrolimus in 15 subjects was studied. The tacrolimus dose to maintain equivalent blood concentrations was lower in CYP3A5*3/*3 than in CYP3A5*1 carriers, and the C/D ratio was significantly higher in the latter. Thus, CYP3A5 polymorphism information played a role in determining the initial dose of tacrolimus. Furthermore, since the effect of tacrolimus appears earlier in CYP3A5*3/*3 than in CYP3A5*1/*1 and *1/*3, it seems necessary to change the evaluation time of therapeutic effect by CYP3A5 genotype. Additionally, the relationship between CYP3A5 genotype and C/D ratio of tacrolimus in colonic mucosa was investigated in 10 subjects. Tacrolimus concentration in the mucosa was two-fold higher in CYP3A5*3/*3 than in CYP3A5*1 carriers, although no significant difference in tacrolimus-blood levels was observed. Therefore, the local concentration of tacrolimus affected by CYP3A5 polymorphism might be related to its therapeutic effect

Türkçeden garp dillerine tercümeler

Taha Toros Arşivi, Dosya Adı: Namık Kemalİstanbul Kalkınma Ajansı (TR10/14/YEN/0033) İstanbul Development Agency (TR10/14/YEN/0033

Role of mTOR Inhibitors in Kidney Disease

The first compound that inhibited the mammalian target of rapamycin (mTOR), sirolimus (rapamycin) was discovered in the 1970s as a soil bacterium metabolite collected on Easter Island (Rapa Nui). Because sirolimus showed antiproliferative activity, researchers investigated its molecular target and identified the TOR1 and TOR2. The mTOR consists of mTOR complex 1 (mTORC1) and mTORC2. Rapalogues including sirolimus, everolimus, and temsirolimus exert their effect mainly on mTORC1, whereas their inhibitory effect on mTORC2 is mild. To obtain compounds with more potent antiproliferative effects, ATP-competitive inhibitors of mTOR targeting both mTORC1 and mTORC2 have been developed and tested in clinical trials as anticancer drugs. Currently, mTOR inhibitors are used as anticancer drugs against several solid tumors, and immunosuppressive agents for transplantation of various organs. This review discusses the role of mTOR inhibitors in renal disease with a particular focus on renal cancer, diabetic nephropathy, and kidney transplantation

Involvement of autophagy in the pharmacological effects of the mTOR inhibitor everolimus in acute kidney injury.

Inhibitors of mammalian target of rapamycin (mTOR) have immunosuppressive and anti-cancer effects, but their effects on the progression of kidney disease are not fully understood. Using cells from normal kidney epithelial cell lines, we found that the antiproliferative effects of mTOR inhibitor everolimus accompanied the accumulation of a marker for cellular autophagic activity, the phosphatidylethanolamine-conjugated form of microtubule-associated protein 1 light chain 3 (LC3-II) in cells. We also showed that the primary autophagy factor UNC-51-like kinase 1 was involved in the antiproliferative effects of everolimus. Levels of LC3-II decreased in the kidneys of rats treated with ischemia-reperfusion or cisplatin; however, renal LC3-II levels increased after administration of everolimus to rats subjected to ischemia-reperfusion or cisplatin treatment. Simultaneously, increased signals for kidney injury molecule-1 and single-stranded DNA and decreased signals for Ki-67 in the proximal tubules were observed after treatment with everolimus, indicating that everolimus diminished renal function after acute tubular injury. We also found leakage of LC3 protein into rat urine after treatment with everolimus, and urinary LC3 protein was successfully measured between 0.1 and 500ng/mL by using an enzyme-linked immunosorbent assay. Urinary LC3 levels were increased after administration of everolimus to rats subjected to ischemia-reperfusion or cisplatin treatment, suggesting that renal LC3-II and urinary LC3 protein are new biomarkers for autophagy in acute kidney injury. Taken together, our results demonstrated that the induction of autophagy by everolimus aggravates tubular dysfunction during recovery from kidney injury

Urinary dopamine as a potential index of the transport activity of multidrug and toxin extrusion in the kidney

Dopamine is a cationic natriuretic catecholamine synthesized in proximal tubular cells (PTCs) of the kidney before secretion into the lumen, a key site of its action. However, the molecular mechanisms underlying dopamine secretion into the lumen remain unclear. Multidrug and toxin extrusion (MATE) is a H+/organic cation antiporter that is highly expressed in the brush border membrane of PTCs and mediates the efflux of organic cations, including metformin and cisplatin, from the epithelial cells into the urine. Therefore, we hypothesized that MATE mediates dopamine secretion, a cationic catecholamine, into the tubule lumen, thereby regulating natriuresis. Here, we show that [3H]dopamine uptake in human (h) MATE1-, hMATE-2K- and mouse (m) MATE-expressing cells exhibited saturable kinetics. Fluid retention and decreased urinary excretion of dopamine and Na+ were observed in Mate1-knockout mice compared to that in wild-type mice. Imatinib, a MATE inhibitor, inhibited [3H]dopamine uptake by hMATE1-, hMATE2-K- and mMATE1-expressing cells in a concentration-dependent manner. At clinically-relevant concentrations, imatinib inhibited [3H]dopamine uptake by hMATE1- and hMATE2-K-expressing cells. The urinary excretion of dopamine and Na+ decreased and fluid retention occurred in imatinib-treated mice. In conclusion, MATE transporters secrete renally-synthesized dopamine, and therefore, urinary dopamine has the potential to be an index of the MATE transporter activity

Riluzole prevents oxaliplatin-induced cold allodynia via inhibition of overexpression of transient receptor potential melastatin 8 in rats

Oxaliplatin causes acute cold hypersensitivity in most patients. We previously reported oxalate derived from oxaliplatin induced cold allodynia via overexpression of transient receptor potential melastatin 8 (TRPM8) in the dorsal root ganglion (DRG) in rats. In this study, we examined the effect of riluzole on oxaliplatin-induced cold allodynia. In cultured DRG neurons, riluzole suppressed oxalate-induced increase of the number of menthol (TRPM8 agonist)-sensitive cells. Moreover, riluzole prevented cold allodynia and increase in levels of TRPM8 mRNA in oxaliplatin-treated rats. These results suggest that riluzole prevents oxaliplatin-induced cold allodynia via inhibition of TRPM8 overexpression in the DRG. Keywords: Oxaliplatin-induced cold allodynia, Riluzole, TRPM

Effect of CYP2C19 polymorphisms on the clinical outcome of low-dose clobazam therapy in Japanese patients with epilepsy.

[Purpose]Clobazam (CLB) is metabolized by cytochrome P450 (CYP) 3A4 to yield N-desmethylclobazam (N-CLB), which is further inactivated by CYP2C19. The aim of this study was to retrospectively evaluate the relationship between CYP2C19 polymorphisms and the efficacy of low-dose, add-on CLB therapy in Japanese patients with epilepsy. [Methods]Fifty patients were divided into three groups according to their CYP2C19 polymorphism. CLB and N-CLB serum concentrations and seizure frequency before and after starting CLB were analyzed. [Results]Extensive metabolizers (EMs, n = 11), intermediate metabolizers (IMs, n = 22), and poor metabolizers (PMs, n = 17) were included. Although the dose-normalized CLB serum concentrations were not significantly different, the dose-normalized N-CLB serum concentrations were significantly higher in PMs than in EMs or IMs. Seizure frequency was significantly decreased by the CLB therapy in PMs (p < 0.01), but not in EMs or IMs. CLB serum concentrations did not correlate with seizure reduction rate, but median N-CLB serum concentrations were significantly higher in patients with excellent seizure control (≧90 % seizure reduction) compared to those with ≧50 % seizure reduction or with <50 % seizure reduction (1103, 341, and 570 ng/mL, respectively). [Conclusions]The efficacy of low-dose CLB therapy was significantly influenced by CYP2C19 polymorphisms. Ideally, CLB therapy should be started with a low dose (2.5 mg/day) and dosage increased until N-CLB serum concentration reaches 1100 ng/mL or until the desired effect is acquired, a recommendation that is particularly important for PMs