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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).
Ototoxicity
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
Platinum can be detected in hair cells, spiral ganglion neurons and at particularly high levels in SV following repeated systemic administration of cisplatin.173 Transport proteins megalin (LRP2), the organic cation transporter OCT2 (also known as SLC22A2) and the copper uptake transporter Ctr1 (SLC31A1) are thought to play roles in cellular entry of cisplatin. Ctr1 has been localized to hair cells, the SV and spiral ganglion cells in mice.120,153 Variations in the gene encoding megalin and that of Ctr1174 have been associated with the severity of cisplatin ototoxicity, but the small size of the populations assessed requires caution in interpreting these results.17 The uptake of the drug to strial marginal cells would assist potential entry into endolymph and this may be a crucial factor for access to hair cells.153,154,159 A rapid deterioration in the auditory nerve response threshold is produced when cisplatin is present in the scala media at concentrations of about 5 mM, but no effect is apparent with perilymphatic perfusion at drug concentrations of less than 3 mM.175 This suggests that one possible site of the drug action is at the apical end of the hair cells. Cisplatin has been shown to be able to block transduction currents in isolated hair cells from chicken,176 and functional mechanotransduction channels have been shown to be required for uptake of fluorescently labelled cisplatin into hair cells in neuromasts of zebra-fish lateral line (a model system for screening for ototoxic drugs).177 Thus, it is possible that, like aminoglycosides, cisplatin gains entry to endolymph from the SV, and an affinity for the hair cell transduction channel may underlie its specific action upon hair cells, but there is no conclusive evidence for this.
Effects of single-nucleotide polymorphism on the pharmacokinetics and pharmacodynamics of metformin
Published in Expert Review of Clinical Pharmacology, 2022
Shaoqian Li, Bo Xu, Shangzhi Fan, Bo Kang, Lijing Deng, Danjun Chen, Bo Yang, Fan Tang, Zunbo He, Yong Xue, Jie-Can Zhou
The contribution of genetic variants of Slc22a2 to the pharmacokinetics of metformin has been evaluated, particularly their effect on renal elimination. Compared with the reference genotype, the genetic variation (T199I, T201M and A270S) in Slc22a2 showed significant differences in metformin pharmacokinetics with a lower clearance, indicating that reduced transport function associated with the Slc22a2 variant leads to decreases the renal clearance of metformin, which leads to aggrandized plasma concentrations [61]. In addition, the expression of OCT2 in the kidney is related to gender. The expression level of male rats was higher than that of female rats [62,63]. Moreover, studies on rats have found that testosterone increases, whereas estrogen decreases Oct2 expression in the kidney [62,64]. All the existing OCT2 polymorphisms affect the clearance of metformin. This evidence suggests that OCT2 gene polymorphisms in different populations can change the body’s ability to absorb and clear drugs. However, the expression level of OCT2 in different genders, which causes the variation in the absorption and clearance of metformin, has not been reported(Table 3).
Impact of DNA methylation on ADME gene expression, drug disposition, and efficacy
Published in Drug Metabolism Reviews, 2022
Xu Hao, Yuanyuan Li, Jialu Bian, Ying Zhang, Shiyu He, Feng Yu, Yufei Feng, Lin Huang
SLC22A2 and SLC22A5 are responsible for the cellular uptake of oxaliplatin (Qu et al. 2013; Liu et al. 2016), and ABCG2 is an important efflux transporter. As mentioned above, Moon et al. also found that 5-Aza-dC potentiated the cell viability together with oxaliplatin in SNU-C4, LS174T, NCI-H716 cells, where ABCG2 gene expression was low and promoter methylation was high (Moon et al. 2016). Chen and Liu et al. verified that hypermethylation of the SLC22A2 promoter methylation inhibited OCT2 expression in renal cell carcinoma cells. Treatment with decitabine (DAC) activated the expression of OCT2 and increased the accumulation and sensitivity of oxaliplatin (Liu et al. 2016; Chen, Wang, et al. 2020). Application of DAC to HepG2 and LS174T cells reversed the SLC22A5 promoter hypermethylation and increased OCTN2 expression, enhancing cellular uptake of oxaliplatin (Qu et al. 2013).
Prediction, diagnosis, prevention and treatment: genetic-led care of patients with diabetes
Published in Expert Review of Precision Medicine and Drug Development, 2021
Watip Tangjittipokin, Nutsakol Borrisut, Patcharapong Rujirawan
Metformin. Metformin is one of the most used drugs for T2DM and is recommended as first-line therapy. Genetic variations associated with pharmacokinetics, tissue uptake, and clearance have been identified as SLC22A1, SLC22A2, and SLC47A, however, use in clinical practice remains limited [94]. GWAS of metformin response also shows that variations in ATM/NPAT and SLC2A2 loci can influence glycemic response to metformin. The rs11212617 near ATM locus is linked with glycemic response to metformin in some populations [95]. Data in the analysis of gene expression in liver samples indicate that the rs8192675 variant in SLC2A2 encoding GLUT-2 has a robust association with metformin-induced HbA1c reduction and reduced SLCA2A expression causes a defect in glucose homeostasis in T2DM, which could be ameliorated by metformin treatment [95,96]. Nonetheless, there is no association of variants in ATM or SLC2A2 in drug response in prediabetic patients [95,97].