Читать книгу Drug Transporters - Группа авторов - Страница 132

In addition to their clear pharmacological importance as mediators of drug disposition and pharmacokinetics, environmental toxins are also transported by the Oats, including ochratoxin A, aristolochic acid, perfluoroctanoic acid, and mercury conjugates [23, 24]. Furthermore, the OATs, particularly OAT1 and OAT3, appear to play a major role in the disposition of uremic toxins. Uremic toxins are small molecules that are elevated in the blood of patients with chronic kidney disease (CKD). Metabolomics data from Oat1 and Oat3 null mice demonstrate the accumulation of uremic toxins in the blood of mice lacking these transporters [120, 121,152–154] These studies have also noted the accumulation of uremic toxins derived from the gut microbiome, which is particularly relevant as the importance of mammalian–microbiome interactions in conditions including cancer, diabetes, obesity, inflammatory bowel disease, and autoimmune diseases becomes increasingly clear [155]. The inability to clear these compounds can also lead to pathophysiological states in remote organs, as the accumulation of indoxyl sulfate, a high‐affinity OAT1 and OAT3 substrate, has been associated with cardiovascular risk [156]. Thus, it is important to understand how disease states, as well as the administration of drugs cleared through OATs impact the circulating levels of uremic toxins.

Interestingly, CKD not only leads to a progressive loss in the ability of the kidney to handle and eliminate drugs and metabolites, but it also alters the disposition of drugs and metabolites handled by non‐renal tissues, particularly the liver [157]. Indeed, renal and non‐renal Oat expression and function in CKD animal models has been shown to be altered [76]. Impairment of liver function, such as that caused by cholestasis, also alters drug handling and the expression of transporters in the kidney [158]. In support of this notion, studies using Oat knockout animals suggest a possible role for these transporters in blood pressure regulation, diabetic ketoacidosis, and hepatic steatosis [4, 48, 51, 129].