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PCR primer design for detection of SNPs in SLC22A1 rs683369 encoding OCT1 as the main transporter of metformin
Published in Elida Zairina, Junaidi Khotib, Chrismawan Ardianto, Syed Azhar Syed Sulaiman, Charles D. Sands, Timothy E. Welty, Unity in Diversity and the Standardisation of Clinical Pharmacy Services, 2017
A.A. Mukminatin, V.D.A. Ningrum, R. Istikharah
Metformin is a strong base and exists as >99.9% cation at physiological pH (Christensen et al. 2011). Therefore, it needs a transporter to penetrate the hepatocyte membrane as its action target (Graham et al. 2011). It is widely acknowledged that the main transporter of metformin is Organic Cation Transporter 1 (OCT1) encoded by the SLC22A1 gene located on chromosome 6 and consisting of 11 exons spanning 37 kb. Polymorphisms of SLC22A1 gene are known to cause varied mechanisms of the body response to metformin, which is one of the substrates of the transporter (Jacobs et al. 2014), and can increase diabetes risk factors by 31% (Jablonski et al. 2010). One of the SLC22A1 genetic polymorphisms is the missense SNP rs68339 that leads to the conversion of guanine base into cytosine (Jablonski et al. 2010). These genetic variations affect the effectiveness of metformin pharmacokinetics and appear as one of the biomarkers of metformin efficacy and tolerability. The calculated MAF (Minor Allele Frequency) from few researches 0.339 (Schweighofer et al. 2014), 0.217 (Kim et al. 2009), and 0.22 (Kerb et al. 2002). This variation has also been identified and located in all ethnic groups (African American, European American, Asian American, Mexican American, Pacific Islander) with 13% frequency (Shu et al. 2003).
Rilpivirine
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
It is worth noting, however, that in vitro studies have identified multiple other enzymes and drug transporters that may have some clinical impact on RPV efficacy or toxicity, although so far none has been seen. The human constitutive androstane receptor and its splice variants were activated by RPV and increased the expression of its target gene, CYP2B6 (Sharma et al., 2015); CYP2B6 is not considered to be relevant to RPV pharmacokinetics. RPV inhibited several drug transporters in vitro, including ABCB1, SLC22A1, and SLC22A2, but only at RPV levels far above those seen in patient plasma after a standard 25-mg dosing regimen. However, one study suggested that SLC22A1 might contribute to variability in RPV exposure, and interactions of RPV with substrates of SLC22A1, SLC22A2, or ABCB1 may be possible under some circumstances (Moss et al., 2013). Weiss and Haefeli (2013) studied the impact of RPV on multiple human enzyme targets including P-glycoprotein, breast-cancer resistance protein, and the organic anion-transporting polypeptides (OATPs) 1B1 and OATP1B3. The concentrations required for RPV effects on these entities ranged from 1.3 to 13μM, more than an order of magnitude above the RPV levels seen in patients (~ 0.43 nM). Based on these data these authors concluded that “owing to [RPV’s] low plasma concentrations it is most likely less prone to drug-drug interactions than older NNRTIs” (Weiss and Haefeli, 2013).
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Primary resistance or refractoriness to either of the TKIs appear to be very rare and when seen may be related to poor drug compliance, poor gastrointestinal absorption, p450 cytochrome polymorphisms, interactions with other medications, and abnormal drug efflux and influx at the cellular level.117 In the case of imatinib, in a small cohort of patients, a correlation between the solute carrier family 22 (organic cation transporter), member 1 (SLC22A1, also termed OCT1) expression and response was been observed: The higher the levels of OCT-1, the better the molecular responses. Clearly, it is prudent to confirm compliance in all patients in whom resistance is suspected because clinical outcome is known to be adversely affected when adherence is less than 90%.
Platelets for advanced drug delivery in cancer
Published in Expert Opinion on Drug Delivery, 2023
Daniel Cacic, Tor Hervig, Håkon Reikvam
Several studies have used platelets as a delivery system by loading cytotoxic compounds and the most commonly used drug is DOX [124–129]. However, other chemotherapeutics have also been tested in use with platelet hybrid vesicles [130,131]. Because anthracyclines passively permeate lipid membranes, drug loading is uncomplicated [132]; however, human organic cation transporter 1 (OCT1; SLC22A1)-mediated transport has also been reported [133]. Administering DOX-loaded platelets increased drug uptake and apoptosis induction in Raji cells compared with free DOX [124]. Furthermore, toxicity in cardiomyocytes was reduced, which may have clinical relevance, as cardiomyopathy is a feared consequence of DOX treatment. Platelets have migratory capabilities [134], which were further enhanced by coating DOX-loaded platelets with polydopamine to increase tumor infiltration and drug transfer in MCF-7 breast cancer-bearing mice upon irradiation with near-infrared light [129]. One possible challenge of using platelets as drug vectors is their limited storage potential. Wu et al. used cryopreserved DOX-loaded platelets from clinical-grade platelet concentrates to study apoptosis induction in cell-lines from different solid cancers, creating an ‘off-the-shelf product’ [126]. Cryopreservation of DOX-loaded platelets did not markedly impair platelet function or the cytotoxic effect, which was generally in line with that of free DOX, although it was higher than that of liposomal DOX. Moreover, drug release, although partially a time-dependent and pH-sensitive process, was stimulated by tissue factor-expressing cancer-derived EVs.
Targeting adverse effects of antiseizure medication on offspring: current evidence and new strategies for safety
Published in Expert Review of Neurotherapeutics, 2023
Leihao Sha, Xihao Yong, Zhenhua Shao, Yifei Duan, Qiulei Hong, Jifa Zhang, Yunwu Zhang, Lei Chen
ASMs can be transported across the placental and blood-milk barriers. However, not all reported transporters (especially the dominant transporters) of ASMs are expressed in the placenta or blood-milk barrier (Table 2). For example, the dominant lamotrigine transporter SLC22A1 (OCT1) has no placental expression[44,62], and the expression of other lamotrigine transporters in the placental barrier is relatively low. Based on existing evidence, it is speculated that many unreported placental transporters may be involved in the transport process of ASMs and play an important role. Therefore, identifying ASM transporters of ASMs on the placenta through key binding sites between existing transporters and ASMs is very important for understanding the trans-barrier transport mechanism of ASMs. SLC22A1 is a confirmed dominant transporter of lamotrigine and could be a good example for use in molecular simulations. Taking lamotrigine as an example, based on the reported lamotrigine-SLC22A1 binding amino acid residues[63], we performed amino acid sequence alignment and structural alignment. We found that the transporters SLC22A3, SLC22A5, and SLC22A11, which are highly expressed in the placental and blood-milk barriers, resembled in structure to the dominant transporter SLC22A1 and thus might be involved in the placental and blood-milk barrier transport of lamotrigine (Figure 3).
Sorafenib for hepatocellular carcinoma: potential molecular targets and resistance mechanisms
Published in Journal of Chemotherapy, 2022
Organic cation transporter-1 (OCT1) plays the most important role in sorafenib uptake. OCT1 at the plasma membrane is related to superior results in sorafenib-treated patients [14]. Drug uptake reduction can lead to resistance. SLC22A1 down-regulation encoding solute carrier OCT1 has been found unable to transport sorafenib. The two SLC22A1 variants, R61S fs*10 and C88A fs*16 abolished OCT1-mediated uptake of substrate tetraethylammonium and leads to a reduction in sorafenib sensitivity [15]. The higher expression of breast cancer resistance protein has been found in HCC and responsible for sorafenib efflux. Increased activity of HER3 (human epidermal growth factor receptor 3) pathways reduced the sensitivity to sorafenib, and high levels of p-MET (phosphorylated mesenchymal epithelial transition) reduced clinical response [16].