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Role of Transport in Chemically-Induced Nephrotoxicity *
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Organic cations (e.g., tetraethylammonium [TEA]) are transported rapidly by proximal tubular cells. The anatomical localization of this transport is similar to that for PAH, although not as well characterized. McKinney (1982) demonstrated in the rabbit that the S2 and S3 cells are most active for cation transport. It is likely that species differences also exist with respect to localization of cation transport, although detailed studies have not been forthcoming. As noted above, organic cation and anion transport systems are completely separate. Other cations such as N-methylnicotinamide or quinine will inhibit cation transport, but not alter anion transport. Phenoxybenzamine produces an irreversible inhibition of cation transport, apparently by binding covalently to the transporter. An irreversible inhibitor of PAH transport has not been found. DNP also inhibits the transport of TEA, but this effect is related totally to the inhibition of energy metabolism. Cyanine 863 also blocks selectively organic cation transport competitively at low doses, and, perhaps, noncompetitively at high doses.
The Li+/Na+ Countertransport in Hypertension
Published in Antonio Coca, Ricardo P. Garay, Ionic Transport in Hypertension: New Perspectives, 2019
Among the various alterations of cation transport reported in hypertension, the increase of red cell Li+/Na+ CT is that which has been most widely investigated and confirmed. Moreover, it raised interest in the study of cation transport in hypertension.
Pharmacogenomics of drugs used to treat brain disorders
Published in Expert Review of Precision Medicine and Drug Development, 2020
The effective treatment of BD requires, along its clinical course, antidepressants, antipsychotics, benzodiazepines, anticonvulsants and anti-manic agents [74]. Lithium (1, 2, 3-Propanetricarboxylic acid, 2-hydroxy-trilithium salt tetrahydrate) is the gold-standard for treatment of BD. The mechanism of action of lithium is unclear. Lithium may alter cation transport across cell membrane in nerve and muscle cells and influence reuptake of serotonin and/or norepinephrine. Lithium also inhibits second messenger systems involving phosphatidylinositol cycle. Postsynaptic D2 receptor supersensitivity is also inhibited by lithium [8, 9]. Lithium, acting via inhibition of glycogen synthase kinase-3 (GSK3β), induces the transcription and expression of neurotrophic proteins which subsequently activate cell survival signaling cascades through the phosphatidylinositol 3-kinase (PI3K) pathway. Lithium alters the expression of 236 genes in BP patients. Gene variants and changes in DNA methylation may condition the therapeutic effects of lithium [75]. The PGx of lithium is very complex; however, available data suggest that a series of gene variants affect lithium pharmacokinetics and pharmacodynamics. The following polymorphic variants deserve special attention: BCR: Asn796Ser; BDNF: C/G (rs988748) and G/A (Val66Met); CACNG2: rs2284017, rs2284018, rs5750285; GSK3B: T-50C (GSK3-beta*C); INPP1: C973A (rs1882891); MT-DNA: 10398A (better response to lithium); and NTRK2: rs1387923, rs1565445. Other genes that may affect the response to lithium include ABCG2, CCND1, CREB1, DRD1, ESR1, FMR1, GRIK2, IMPA1, IMPA2, NR3C1, PTGES, SLC6A4 and VEGFA [8, 9, 76].
In silico models to predict tubular secretion or reabsorption clearance pathway using physicochemical properties and structural characteristics
Published in Xenobiotica, 2022
Navid Kaboudi, Ali Akbar Alizadeh, Ali Shayanfar
The excretion of drugs and their metabolites by kidneys plays a vital role in drug elimination, especially for drugs with negligible metabolic, and biliary clearances (Varma et al. 2009). Renal excretion is a net result of several processes, which are active secretion, glomerular filtration, and tubular reabsorption. Secretion of drugs is an active process which transporters secrete drugs from blood into the renal tubule. It is mediated by organic anion and cation transport systems. Glomerular filtration is a passive process, and the filtration clearance equals the product of the glomerular filtration rate, and the fraction of unbound drug in the blood, while tubular reabsorption mostly rely on the passive permeability (Watanabe et al. 2019).
Pharmacological management of atrial fibrillation in patients with heart failure with reduced ejection fraction: review of current knowledge and future directions
Published in Expert Review of Cardiovascular Therapy, 2020
Dofetilide is a class III AA medication that acts on the delayed rectifier potassium current, specifically through blockade of the ion channel responsible for the rapid component of this current [94]. This increases the refractoriness in atrial and ventricular myocytes [95]. Dosing of the drug requires careful monitoring of the QTc due to the risk of torsades de points (TdP). As a renally cleared medication, kidney function must be routinely monitored with appropriate dose adjustment or discontinuation. It exhibits multiple significant drug–drug interactions, particularly with renal cation transport inhibitors (cimetidine, trimethoprim, ketoconazole) which impair its excretion [96].