Drug Transporters. Группа авторов

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0.75 0.07 0.69 0.22 0.37 0.00 0.38 0.12 SLC22A16 CT2 p.His49Arg p.Met409Thr p.Val252Ala 0.22 0.23 0.09 0.37 0.04 0.11 0.23 0.12 0.12 0.42 0.00 0.07 0.28 0.11 0.07

      Abbreviations:

      EUR = European

      AFR = African

      AMR = Ad mixed American

      EAS = East Asian

      SAS = South Asian

      2.3.5 Biomarkers and FDA Guidances for Transporter‐Mediated DDIs

      Polypharmacy commonly exists in older and chronic disease populations. Transporters can interact with a wide range of endogenous and xenobiotic substrates. Significant drug–drug interactions (DDI) can lead to unfavorable efficacy and safety concerns, and therefore, industry, academia, and regulatory agencies have increased the recognition of transporter‐mediated drug interactions. In 2010, the ITC proposed seven transporters as sites for DDIs including P‐gp, BCRP, OATP1B1 and 1B3, OAT1 and 3, and OCT2 [37], which was updated to include MATEs. More recently, the ITC suggested that OCT1 and OATP2B1 be added [38]. The FDA cites manuscripts from the ITC recently published DDI guidance documents, including one focused on in vitro DDI assessment and the other focused on clinical DDI evaluation. These guidances describe the conduct of in vitro transporter studies and the use of specific criteria to assess the potential for drugs to interact with transporters and either perpetrate DDIs or be subjected to DDIs. More recently, potential endogenous biomarkers for transporters are being explored as an additional approach to assess the DDI liability of drug candidates [39]. For OCTs, potential biomarkers, which may lack specificity for individual OCT isoforms, include NMN, tryptophan, and creatinine in addition to thiamine [39]. Full assessment of the biosynthesis and elimination pathways of these compounds as well as extensive studies validating their specificity and usefulness in predicting clinical DDIs are needed.

      2.4.1 Substrate and Inhibitor Selectivity

      2.4.2 Regulation

      Like hOCT1, the activity of human OCT2 can be regulated by protein kinase pathways. PKA stimulation inhibits the uptake of ASP+ by OCT2 expressing cells and the activation of PKC inhibits the basolateral ASP+ uptake in human proximal tubules [2]. hOCT2 is also inhibited by PI3K and activated by a CaM‐dependent signaling pathway, probably via a change in substrate affinity [2]. Moreover, tyrosine kinase inhibitors inhibit the Src family kinase Yes1, which was found to be essential for OCT2 tyrosine phosphorylation and function [2]. In addition, the expression of OCT2 can be regulated by sex hormones. Treatment of male and female rats with testosterone significantly increases the expression levels of rOCT2 mRNA and protein in the kidney, whereas estradiol treatment moderately decreases the expression levels of rOCT2. In accordance with increased OCT2 expression, treatment with testosterone significantly stimulates the TEA accumulation by renal slices in rats of both sexes, whereas estradiol treatment causes a decrease in the TEA accumulation by slices from male, but not female rats [41].

      2.4.3 Animal Models

      Oct2 −/− mice are viable and fertile, showing no apparent physiological defects [42]). However, because Oct1 is also highly expressed in rodent kidney, it has been necessary to generate Oct1/2 −/− double‐knockout mice as a model for the effect of OCT2 on renal drug clearance in humans. The Oct1/2 −/− mice, as with each of the single‐knockouts, is compatible with normal physiology (i.e., normal viability, fertility, and lifespan are observed, with no apparent physiological abnormalities) [42]. However, unlike the single‐knockouts, Oct1/2 −/− mice show significant impairment in the active tubular secretion of organic cations in the kidney. Specifically, renal tubular secretion of TEA is effectively abolished in Oct1/2 −/− mice, with renal clearance approximating glomerular filtration [42]. Consequently, these mice exhibit significantly elevated plasma levels of TEA compared with wild‐type or Oct1 −/− single‐knockout mice. After steady‐state infusion of TEA, plasma levels are elevated approximately 6‐fold in the Oct1/2 −/− double‐knockout mice compared to Oct1 −/− , Oct2 −/− , or wild‐type mice [42]. In mice, OCT1/OCT2 deficiency or coadministration of OCT2 inhibitors (e.g., cimetidine) protects from cisplatin‐induced nephrotoxicity [43].

      2.4.4 Human Genetic Studies

      Though a number of missense polymorphisms have been identified in OCT2 in ancestrally diverse populations, in general, these have not been consistently associated with interindividual variation in drug response. For example, several of the OCT2 missense variants including p.M165I, p.R400C, p.K432Q, and p.A270S exhibit changes in the kinetics of interaction with various substrates and inhibitors in comparison to the reference allele of OCT2 [44]. The single nucleotide insertion variant (c.134‐135insA) resulted in an early stop codon and complete loss of function. Unexpectedly, the rare variants, p.P54S, p.F161L, p.M165V, and p.A297G, retained similar uptake activity for MPP+ as reference OCT2 [45]. As noted, though clinical studies suggest that SLC22A2 variants are associated with metformin disposition and response, cisplatin toxicity, as well as with levels of a variety of endogenous metabolites in humans, many of the results have been conflicting, suggesting small effects of OCT2 variants in clinical pharmacologic studies [2, 34]. Further investigation is warranted.

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