Читать книгу Drug Transporters - Группа авторов - Страница 42

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.