ReviewImpact of Genetic Polymorphisms of Transporters on the Pharmacokinetic, Pharmacodynamic and Toxicological Properties of Anionic Drugs
Summary:
As the importance of drug transporters in the clinical pharmacokinetics of drugs is recognized, genetic polymorphisms of drug transporters have emerged as one of the determinant factors to produce the inter-individual variability of pharmacokinetics. Many clinical studies have shown the influence of genetic polymorphisms of drug transporters on the pharmacokinetics and subsequent pharmacological and toxicological effects of drugs. The functional change in a transporter in clearance organs such as liver and kidney affects the drug concentration in the blood circulation, while that in the pharmacological or toxicological target can alter the local concentration at the target sites without changing its plasma concentration. As for the transporters for organic anions, some single nucleotide polymorphisms (SNPs) or haplotypes occurring with high frequency in organic anion transporting polypeptide (OATP) 1B1, multidrug resistance 1 (MDR1), and breast cancer resistance protein (BCRP) have been extensively investigated in both human clinical studies and in vitro functional assays.
We introduce some examples showing the relationship between haplotypes in transporters and pharmacokinetics and pharmacological effects of drugs. We also discuss how to predict the effect of functional changes in drug transporters caused by genetic polymorphisms on the pharmacokinetics of drugs from in vitro data.
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Refinement of safety and efficacy of anti-cancer chemotherapeutics by tailoring their site-specific intracellular bioavailability through transporter modulation
2023, Biochimica et Biophysica Acta - Reviews on CancerLow intracellular bioavailability, off-site toxicities, and multi drug resistance (MDR) are the major constraints involved in cancer chemotherapy. Many anticancer molecules fail to become a good lead in drug discovery because of their poor site-specific bioavailability. Concentration of a molecule at target sites is largely varied because of the wavering expression of transporters. Recent anticancer drug discovery strategies are paying high attention to enhance target site bioavailability by modulating drug transporters. The level of genetic expression of transporters is an important determinant to understand their ability to facilitate drug transport across the cellular membrane. Solid carrier (SLC) transporters are the major influx transporters involved in the transportation of most anti-cancer drugs. In contrast, ATP-binding cassette (ABC) superfamily is the most studied class of efflux transporters concerning cancer and is significantly involved in efflux of chemotherapeutics resulting in MDR. Balancing SLC and ABC transporters is essential to avoid therapeutic failure and minimize MDR in chemotherapy. Unfortunately, comprehensive literature on the possible approaches of tailoring site-specific bioavailability of anticancer drugs through transporter modulation is not available till date. This review critically discussed the role of different specific transporter proteins in deciding the intracellular bioavailability of anticancer molecules. Different strategies for reversal of MDR in chemotherapy by incorporation of chemosensitizers have been proposed in this review. Targeted strategies for administration of the chemotherapeutics to the intracellular site of action through clinically relevant transporters employing newer nanotechnology-based formulation platforms have been explained. The discussion embedded in this review is timely considering the current need of addressing the ambiguity observed in pharmacokinetic and clinical outcomes of the chemotherapeutics in anti-cancer treatment regimens.
Association of ABCB1, ABCG2 drug transporter polymorphisms and smoking with disease risk and cytogenetic response to imatinib in chronic myeloid leukemia patients
2023, Leukemia ResearchDespite acceptable results of imatinib in the treatment of chronic myeloid leukemia (CML), some patients fail to acquire a complete cytogenetic response (CCyR), which may be caused by polymorphisms in the pharmacogenetic genes. The study aimed to evaluate the association of two polymorphisms in the ABCB1 and ABCG2 genes with cytogenetic response to imatinib and the risk of CML development.
We genotyped ABCB1 (c .2677G/T/A) and ABCG2 (c .421C/A) polymorphisms by PCR-RFLP, T-ARMS-PCR methods in 111 patients with CML and 102 sex- and age-matched healthy subjects. CCyR was determined by standard chromosome banding analysis (CBA).
Analysis of polymorphisms showed significant association of ABCG2 c.421CA genotype (p < 0.0001; OR = 0. 17), and ABCG2c.421A allele (p < 0.0001; OR = 0.31) with decreased risk of CML. Moreover, ABCB1c.2677GT- ABCG2c.421CC combined genotype (p = 0.017; OR = 4.20) was associated with increased risk of CML. Analysis of the joint effect of SNP-smoking combination showed that smoker subjects with the ABCB1c.2677GG/GT (p = 0.001; OR = 15.96, p = 0.001; OR = 8.13, respectively) or ABCG2c.421CC genotypes (p = 0.001; OR = 5.82) had the increased risk of CML, while the risk of the CML in non-smokers carrying the ABCG2c.421CA (p < 0.0001; OR = 0. 18) genotype was strongly decreased compared with reference group. Regarding drug response, ABCG2c.421 CC/CA genotypes in the smoker patients were associated with an increased risk of resistance to imatinib (p < 0.0001; OR = 7.02, p = 0.018; OR = 4.67, respectively).
Our results suggest the impact of ABCG2c .421C/A polymorphism on CML development, and smoking may have a synergistic role in the risk of CML and resistance to imatinib.
Drug Transporters: Efflux
2022, Comprehensive PharmacologyEfflux transporters are membrane-bound proteins that pump their substrates out of cells or cellular compartments. Most efflux transporters belong to the ABC superfamily which uses active transport (hydrolysis of ATP) to drive the movement of their substrates across biological membranes. The exceptions to this are MATEs, a subfamily of SLC transporters that use proton gradients to efflux their substrates instead of active transport. While efflux transporters have endogenous substrates, many of them also transport clinically relevant drugs and their metabolites. These transporters are located in multiple organs and tissues including the intestine, liver, kidneys, and blood-tissue barriers. Depending on their localization to either the apical or basolateral membrane of epithelial cells, efflux transporters regulate the movement of drugs into or out of these organs and tissues. Due to their ability to either restrict or facilitate the movement of drugs between systemic circulation and tissues, efflux transporters play important roles in determining drug pharmacokinetics. This article will review the major efflux transporters and their involvement in drug absorption, distribution, and hepatic and renal clearance.
Effect of Genetic Polymorphisms of Human SLC22A3 in the 5’-flanking Region on OCT3 Expression and Sebum Levels in Human Skin
2021, Journal of Dermatological ScienceCitation Excerpt :Previous studies suggested that transporters play a role in in vivo drug pharmacokinetics, while transporter-mediated drug-drug interactions were recently identified [1,2,3,4]. The accumulation of evidence has revealed that variabilities in the expression and activities of some transporters affect pharmacokinetics as well as pharmacological and/or toxicological effects [5,6,7,8]. The skin is the largest organ of the human body.
Human organic cation transporter 3 (OCT3,SLC22A3) mediates the uptake of many important endogenous substances and basic drugs, and has been identified as one of the transporters that are highly expressed in human skin. However, the mechanisms responsible for variability in mRNA expression, and the role of SLC22A3 in human skin is not clear.
We examined the effects of the single nucleotide polymorphisms ofSLC22A3 on the variability in SLC22A3 expression and sebum levels in humans.
Immunostaining of OCT3 in human skin was performed. We analyzed the association of promoter variants with the SLC22A3 mRNA expression levels in human skins. Luciferase, knockdown, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay were employed to investigate transcriptional regulation of SLC22A3 expression. Effects of the identified variant on sebum levels were evaluated in healthy volunteers.
Immunohistochemistry revealed marked expressions of OCT3 in the basal epidermis, sebaceous glands, hair follicles, and sweat glands of human skin. SLC22A3 mRNA levels were significantly lower in skin samples with homozygotes for –1603A/A than in those for −1603 G/G. The analysis of p53 binding to −1603 G > A in the promoter ofSLC22A3 suggested that −1603 G > A down-regulates SLC22A3 gene expression by decreased p53 binding in the vicinity of the –1603 site. In humans, squalene levels in samples from the back at the baseline were significantly lower in homozygotes for –1603A/A than in those for −1603 G/G.
These results suggest that the genetic variant contributes to the variability of expression and activities of OCT3 in human skin.
Membrane transporter data to support kinetically-informed chemical risk assessment using non-animal methods: Scientific and regulatory perspectives
2019, Environment InternationalHumans are continuously exposed to low levels of thousands of industrial chemicals, most of which are poorly characterised in terms of their potential toxicity. The new paradigm in chemical risk assessment (CRA) aims to rely on animal-free testing, with kinetics being a key determinant of toxicity when moving from traditional animal studies to integrated in vitro-in silico approaches. In a kinetically informed CRA, membrane transporters, which have been intensively studied during drug development, are an essential piece of information. However, how existing knowledge on transporters gained in the drug field can be applied to CRA is not yet fully understood. This review outlines the opportunities, challenges and existing tools for investigating chemical-transporter interactions in kinetically informed CRA without animal studies. Various environmental chemicals acting as substrates, inhibitors or modulators of transporter activity or expression have been shown to impact TK, just as drugs do. However, because pollutant concentrations are often lower in humans than drugs and because exposure levels and internal chemical doses are not usually known in contrast to drugs, new approaches are required to translate transporter data and reasoning from the drug sector to CRA. Here, the generation of in vitro chemical-transporter interaction data and the development of transporter databases and classification systems trained on chemical datasets (and not only drugs) are proposed. Furtheremore, improving the use of human biomonitoring data to evaluate the in vitro-in silico transporter-related predicted values and developing means to assess uncertainties could also lead to increase confidence of scientists and regulators in animal-free CRA. Finally, a systematic characterisation of the transportome (quantitative monitoring of transporter abundance, activity and maintenance over time) would reinforce confidence in the use of experimental transporter/barrier systems as well as in established cell-based toxicological assays currently used for CRA.
Imaging techniques to study drug transporter function in vivo
2018, Pharmacology and TherapeuticsTransporter systems involved in the permeation of drugs and solutes across biological membranes are recognized as key determinants of pharmacokinetics. Typically, the action of membrane transporters on drug exposure to tissues in living organisms is inferred from invasive procedures, which cannot be applied in humans. In recent years, imaging methods have greatly progressed in terms of instruments, synthesis of novel imaging probes as well as tools for data analysis. Imaging allows pharmacokinetic parameters in different tissues and organs to be obtained in a non-invasive or minimally invasive way. The aim of this overview is to summarize the current status in the field of molecular imaging of drug transporters. The overview is focused on human studies, both for the characterization of transport systems for imaging agents as well as for the determination of drug pharmacokinetics, and makes reference to animal studies where necessary. We conclude that despite certain methodological limitations, imaging has a great potential to study transporters at work in humans and that imaging will become an important tool, not only in drug development but also in medicine. Imaging allows the mechanistic aspects of transport proteins to be studied, as well as elucidating the influence of genetic background, pathophysiological states and drug-drug interactions on the function of transporters involved in the disposition of drugs.