Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug–drug interactions

Abstract

The SCL22A1 gene encodes the broad selectivity transporter hOCT1. hOCT1 is expressed in most epithelial barriers thereby contributing to drug pharmacokinetics. It is also expressed in different drug target cells, including immune system cells and others. Thus, this membrane protein might also contribute to drug pharmacodynamics. Up to 1000 hOCT1 polymorphisms have been identified so far, although only a small fraction of those have been mechanistically studied. A paradigm in the field of drug transporter pharmacogenetics is the impact of hOCT1 gene variability on metformin clinical parameters, affecting area under the concentration-time curve, Cmax and responsiveness. However, hOCT1 also mediates the translocation of a variety of drugs used as anticancer, antiviral, anti-inflammatory, antiemetic agents as well as drugs used in the treatment of neurological diseases among. This review focuses exclusively on those drugs for which some pharmacogenetic data are available, and aims at highlighting the need for further clinical research in this area.

Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation

“…Although imatinib does not seem to be translocated by human OCT1 (Nies et al, 2014), the polymorphic variants of OCT1 have been several times reported to affect outcome in the treatment of chronic myeloid leukemia (CML). This apparent controversy between human OCT1 polymorphic variants and outcomes of treatment with imatinib has been recently again confirmed in other studies (Angelini et al, 2013;Arimany-Nardi et al, 2015;Crossman et al, 2005). Drugs such as morphine, analgesic drug tramadole metabolite O-desmethyltramadol, and antiemetic drugs tropisetron and ondasetron have also been shown in pharmacogenetic clinical studies to be affected by OCT1 variants (Arimany-Nardi et al, 2015).…”

“…In these individuals carrying SLC22A1 polymorphisms, significantly higher glucose levels after metformin treatment have been associated with higher AUC and C max for metformin (Shu et al, 2007(Shu et al, , 2008. In patients with type II diabetes mellitus, only genetic variation rs622342 has been associated with the glucose-lowering effect of metformin (Becker et al, 2009), although there also exist controversial reports (Arimany-Nardi et al, 2015). Similarly, polymorphism rs622342 A > C has been shown to be associated with poorer drug response to antiparkinson drug levodopa (Becker et al, 2011).…”

“…Since then, over 1000 single-nucleotide polymorphisms have been identified, 22 of which have clinical relevance to drugs belonging to OCT1 substrates and consequences for the treatment outcomes (Arimany-Nardi et al, 2015). Six variants (R61C, F160L, P341L, M408C, G465R and the intronic rs622342) are SNPs with allelic frequencies higher than 1% in some populations (Arimany-Nardi et al, 2015). In addition, 11 haplotypes with frequencies higher than 1% have been identified for SLC22A1 gene (Nies et al, 2009).…”

“…Influence of genetic variability of OCT1 on clinical aspects of pharmacotherapy has been recently summarized in review article by Arimany-Nardi et al (2015). In addition, drug-drug interactions at the level of OCT transporters have been recently reviewed by the ''father'' of OCTs (Koepsell, 2015).…”

Pharmacogenomic implications of the evolutionary history of infectious diseases in Africa

“…For example, pentamidine is transported within the body by human OCT1, a broad selectivity transporter encoded by the highly polymorphic SCL22A1 gene, 117, 118 variants of which affect the efficiency of uptake, distribution, and excretion of clinically relevant drugs. 117, 119, 120 Furthermore, CYP450 enzymes with roles in the metabolism of pentamidine include CYP1A1, CYP1A2, CYP2C8, CYP2C19, CYP2B6, CYP3A4, CYP3A5 and CYP4A11. 81 …”