Genetic Polymorphisms Of Drug Transporters Research Articles

Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation.

This study aimed to analyse the effects of genetic polymorphisms in drug transporters and metabolizing enzymes, and clinical laboratory data on the pharmacokinetic parameters of apixaban. Data were collected from 81 Japanese patients with atrial fibrillation. Pharmacogenomic data were stratified by ABCB1, ABCG2 and CYP3A5 polymorphisms. The pharmacokinetic profile of apixaban was described by a one-compartment model with first-order absorption. Population pharmacokinetic analysis was conducted using a nonlinear mixed effect modelling (NONMEM™) program. The nonlinear relationship between oral clearance (CL/F) of apixaban and creatinine clearance (Ccr) was observed. The population mean of CL/F for a typical patient (Ccr value of 70mlmin-1 ) with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotypes was estimated to be 3.06lh-1 . When Ccr values were set to the typical value, the population mean of CL/F was 1.52 times higher in patients with the CYP3A5*1/*1 genotype compared with patients with the CYP3A5*1/*3 or *3/*3 genotype, while the population mean of CL/F was 1.49 times higher in patients with the ABCG2 421C/C or C/A genotype compared with patients with the ABCG2 421A/A genotype. However, no covariates affected the population mean of the apparent volume of distribution (Vd/F) of apixaban. The population mean of Vd/F was estimated to be 24.7l. The present study suggests that the ABCG2 421A/A and CYP3A5*3 genotypes and renal function are intrinsic factors affecting apixaban pharmacokinetics. These findings may provide useful information for precision medicine using apixaban, to avoid the risk of adverse reactions.

Identification of polymorphic variants associated with erlotinib-related skin toxicity in advanced non-small cell lung cancer patients by DMET microarray analysis.

Erlotinib is a targeted agent commonly used in advanced non-small cell lung cancer (aNSCLC). However, drug-related skin toxicity often may affect the quality of life of cancer patients and lead to treatment discontinuation. Genetic polymorphisms in drug transporters and metabolizing enzymes play a major role in the interindividual variability in terms of efficacy and toxicity of erlotinib treatment. The aim of our study was to identify genetic determinants in adsorption, distribution, metabolism, and excretion genes influencing skin rash (SR) by the novel drug-metabolizing enzyme and transporter (DMET) microarray Affymetrix platform in aNSCLC patients. In a retrospective study, 34 erlotinib-treated aNSCLC patients were genotyped by DMET Plus chip: 23 patients experienced SR (cases), while 11 patients did not (controls). Peripheral blood DNA was genotyped. Genotype association was analyzed by Fisher's exact test, and the toxicity-associated gene sets underwent Ingenuity Pathway Analysis (IPA). Seven SNPs in six genes (CYP27B1, MAT1A1, CHST1, CYP4B1, ADH6, and SLC22A1) were associated with the occurrence of SR or with a protective effect. Specifically, the rs8176345 in CYP27B1 gene was significantly correlated with SR (p = 0.0003, OR 55.55, 95% CI 2.7036-1141.1707). The IPA on SR-related genes highlighted the role of a variety of canonical pathways including 1,25-dihydroxyvitamin D3 biosynthesis, S-adenosyl-L-methionine biosynthesis, and methionine degradation I (to homocysteine) in SR development. Although exploratory, this study indicates rs8176345 in CYP27B1 gene as significantly correlated with erlotinib-induced SR in aNSCLC patients probably through a mechanism mediated by vitamin D3 and inflammation at skin level.

Misoprostol-Induced Fever and Genetic Polymorphisms in Drug Transporters SLCO1B1 and ABCC4 in Women of Latin American and European Ancestry

Misoprostol, a prostaglandin analogue used for the treatment of postpartum hemorrhage and termination of pregnancy, can cause high fevers. Genetic susceptibility may play a role in misoprostol-induced fever. Body temperature of women treated with misoprostol for termination of pregnancy in the UK (n = 107) and for postpartum hemorrhage in Ecuador (n = 50) was measured. Genotyping for 33 single nucleotide polymorphisms in 15 candidate genes was performed. Additionally, we investigated the transport of radiolabeled misoprostol acid across biological membranes in vitro. The ABCC4 single nucleotide polymorphism rs11568658 was associated with misoprostol-induced fever. Misoprostol acid was transported across a blood-brain barrier model by MRP4 and SLCO1B1. Genetic variability in ABCC4 may contribute to misoprostol-induced fever in pregnant women. Original submitted 21 January 2015; Revision submitted 24 April 2015.

The SmartAmp Method: Rapid Detection of SNPs in Thiopurine S-Methyltransferase and ABC Transporters ABCC4 and ABCG2

Genetic polymorphisms of drug transporters as well as drug metabolizing enzymes have been documented to play a significant role in patients' responses to medication. A key requirement for advancing personalized medicine is the ability to rapidly and conveniently test for patients' genetic polymorphisms. We have recently developed a rapid and cost-effective method for single nucleotide polymorphism (SNP) detection, named Smart Amplification Process (SmartAmp), which enables us to detect genetic polymorphisms or mutations in 30 to 45 min under isothermal conditions without the need for DNA isolation and PCR amplification. This article presents the SmartAmp-based detection of SNPs in the thiopurine S-methyltransferase gene as well as in the ATP-binding cassette (ABC) transporter ABCC4 and ABCG2 genes that are critically involved in drug-induced adverse reactions. The SmartAmp method is expected to provide a practical and cost-effective tool for pharmacogenomics-based personalized medicine.

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

It has been reported that organic anion-transporting polypeptide (OATP) 1B1, OATP1B3 and multidrug resistance-associated protein 2 are involved in the hepatobiliary transport of olmesartan. We investigated the association of SLCO1B1, SLCO1B3 and ABCC2 polymorphisms with the pharmacokinetics of olmesartan. We sequenced all exons, exon-intron junctions and the 5' and 3' flanking regions of the three genes in 115 individuals from African-American, Hispanic and Caucasian populations who had participated in our clinical studies. A total of 348 single-nucleotide polymorphisms (SNPs) were identified with a minor allele frequency of ≥0.01 in at least one population; 132 SNPs were detected in SLCO1B1, 130 in SLCO1B3 and 86 in ABCC2. We characterized the linkage disequilibrium (LD) and haplotypes shared across the populations and then evaluated the association between the haplotypes and the pharmacokinetics of olmesartan. Seven inter-ethnic LD blocks were observed in SLCO1B1, while three in SLCO1B3 and four in ABCC2. Although extensive variability in the sequences of SLCO1B1, SLCO1B3 and ABCC2 existed across the three populations, there was no remarkable difference in any pharmacokinetic parameters of olmesartan between subjects with and without any major haplotypes in the three transporter genes we tested.

ChemInform Abstract: Genetic Polymorphisms of SLCO1B1 for Drug Pharmacokinetics and Its Clinical Implications

AbstractReview: 30 refs.

Genetic Polymorphisms of <i>SLCO1B1</i> for Drug Pharmacokinetics and Its Clinical Implications

Various drug transporters are selectively expressed in single or multiple tissues, such as the intestine, liver and kidney, where these transporters play various roles in drug absorption, distribution and excretion. Genetic polymorphisms in drug transporters as well as drug-metabolizing enzymes are associated with interindividual differences in drug disposition, efficacy and toxicity. Organic anion transporting polypeptide 1B1 (OATP1B1, gene SLCO1B1) is expressed on the basolateral membrane of hepatocytes and can facilitate hepatic uptake of certain clinically relevant drugs such as statins except for fluvastatin, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, antidiabetic drug (repaglinide) and anticancer drugs (SN-38 and methotrexate). Some single nucleotide polymorphisms or haplotypes of the SLCO1B1 gene have been identified and demonstrated to have functional significance for transporter activity. For examples, the SLCO1B1*15 haplotype (or 521T>C genotype) results in decreased uptake activity of SN-38 from systemic circulation, leading to increased plasma concentration of SN-38 and an enhanced risk of neutropenia. This review focuses on the impact of genetic polymorphisms of the SLCO1B1 gene on transport activity, and implications for the clinical efficacy and toxicity of clinically useful drugs.

The SLCO1B1 rs4149032 Polymorphism Is Highly Prevalent in South Africans and Is Associated with Reduced Rifampin Concentrations: Dosing Implications

Among patients with tuberculosis, rifampin plasma concentrations and sputum conversion rates have been reported to be lower in Africans. Rifampin is a substrate of P-glycoprotein (coded for by the ABCB1 gene) and organic anion-transporting polypeptide 1B1 (coded for by SLCO1B1). The objectives were to identify genetic polymorphisms of drug transporters and the transcriptional regulators pregnane X receptor (PXR) and constitutive androstane receptor (CAR) with an impact on rifampin pharmacokinetics in South Africans. Fifty-seven patients with tuberculosis from Cape Town underwent pharmacokinetic sampling during treatment with rifampin, pyrazinamide, isoniazid, and ethambutol. DNA was genotyped for ABCB1, SLCO1B1, PXR, and CAR polymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of the SLCO1B1 rs4149032 polymorphism was 0.70. Patients heterozygous and homozygous for this polymorphism had reductions in the bioavailability (and, thus, the area under the curve [AUC]) of rifampin of 18% and 28%, respectively. Simulations showed that increasing the daily rifampin dose by 150 mg in patients with the polymorphism would result in plasma concentrations similar to those of wild-type individuals and reduce the percentage of patients with peak plasma concentrations (C(max)) below 8 mg/liter from 63% to 31%. ABCB1, PXR, and CAR polymorphisms were not associated with differences in rifampin pharmacokinetics. SLCO1B1 rs4149032 was present in most patients and was associated with substantially reduced rifampin exposure. These data suggest that the standard recommended dose of rifampin should be reconsidered for South Africans.

Genetic Polymorphisms of Hepatic ABC-Transporter in Patients with Hepatocellular Carcinoma

We examined whether genetic polymorphisms of efflux transporters in hepatocytes are associated with susceptibility to develop hepatocellular carcinoma (HCC). Genetic polymorphisms of drug transporters expressed in hepatocytes were analyzed using DNA samples from hepatitis C virus (HCV)-seropositive cirrhotic patients with HCC (n = 58), and allele and haplotype frequencies were compared with those in healthy subjects (n = 61). To search for single nucleotide polymorphisms (SNPs) in HCC susceptibility genes, 34 SNPs in 6 efflux transporters [MDR1 (ABCB1), ABCC1, ABCC2, ABCC3, ABCG2 and ABCB11] were determined. No significant association was observed for any single SNP; however, some haplotypes in ABCC1 and ABCB11 were associated with HCC. Furthermore, three combinations of SNPs (3435C > T in ABCB1 and 825T > C in ABCC1), (3435C > T in ABCB1 and -15281_-15278CTCT > delete in ABCB11), and (825T > C in ABCC1 and -15281_-15278CTCT > delete in ABCB11) were significantly associated with HCC. The present study suggests that genetic variations of ABC transporters such as ABCB1, ABCB11, and ABCC1 are associated with susceptibility to develop HCC, implying that aberrant hepatic clearance of toxic substances may increase the risk of hepatocarcinogenesis. Further studies of how these polymor-phisms are associated with phenotypic differences are warranted.

Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs—from bench to bedside

The chronic nature of rheumatoid arthritis (RA) means that patients require drug therapy for many years. Many RA patients, however, have to discontinue treatment because of drug-related toxic effects, loss of efficacy, or both. The underlying molecular cause for loss of efficacy of antirheumatic drugs is not fully understood, but it might be mediated, at least in part, by mechanisms shared with resistance to anticancer drugs. This Review outlines molecular mechanisms that could be involved in the onset of resistance to, or the loss of efficacy of, disease-modifying antirheumatic drugs in RA patients, including methotrexate, sulfasalazine, chloroquine, hydroxychloroquine, azathioprine, and leflunomide. The mechanisms suggested are based on findings from experimental laboratory studies of specific drug-uptake and drug-efflux transporters belonging to the superfamily of multidrug-resistance transporters, alterations in intracellular drug metabolism, and genetic polymorphisms of drug transporters and metabolic enzymes. We also discuss strategies to overcome resistance and the current clinical studies aiming to predict response and risk of toxic effects. More in-depth knowledge of the mechanisms behind these features could help facilitate a more efficient use of disease-modifying antirheumatic drugs.

Genetic polymorphisms of drug transporters: pharmacokinetic and pharmacodynamic consequences in pharmacotherapy

There has been increasing appreciation of the role of drug transporters in pharmacokinetic and pharmacodynamic consequences in pharmacotherapy. The clinical relevance of drug transporters depends on the localisation in human tissues (i.e., vectorial movement), the therapeutic index of the substrates and inherent interindividual variability. With regard to variability, polymorphisms of drug transporter genes have recently been reported to be associated with alterations in the pharmacokinetics and pharmacodynamics of clinically useful drugs. A growing number of preclinical and clinical studies have demonstrated that the application of genetic information may be useful in individualised pharmacotherapy for numerous diseases. However, the reported effects of variants in certain drug transporter genes have been inconsistent and, in some cases, conflicting among studies. Furthermore, the incidence of almost all known variants in transporter genes tends to be racially dependent. These observations suggest the necessity of considering interethnic variability before extrapolating pharmacokinetic data obtained in one ethic group to another, especially in the early phase of drug development. This review focuses on the impact of genetic variations in the function of drug transporters (ABC, organic anion and cation transporters) and the implications of these variations for pharmacotherapy from pharmacokinetic and pharmacodynamic viewpoints.

Implications of genetic polymorphisms in drug transporters for pharmacotherapy

Drug transporters are increasingly recognized as a key determinant of drug disposition and response. It is now widely appreciated that expression of the ATP-dependent efflux transporter, MDR1 ( ABCB1, P-glycoprotein), in organs such as the gastrointestinal tract, liver and kidney significantly alters the extent of drug absorption and excretion. Moreover, expression of MDR1 at the level of the blood–brain barrier limits the entry of many drugs into the central nervous system. Given such an important role of MDR1 in the drug disposition process, it is not surprising to see increasing focus on the role of single nucleotide polymorphisms (SNPs) in this transporter as a potential determinant of interindividual variability in drug disposition and pharmacological response. However, drug transport is often the result of the concerted action of efflux and uptake pumps located both in the basolateral and apical membranes of epithelial cells. A growing list of membrane-spanning proteins involved in the in- or outward transport of a large variety of drugs has been recognized and characterized over the past few years in almost all tissues, including organic anion and cation transporters (OAT, OCT, solute carrier family SLC22 A), organic anion transport proteins (OATP, solute carrier family SLCO, formerly SLC21 A), and MRPs ( ABCCs), other members of the ATP-binding cassette family. We are just beginning to appreciate their role for drug delivery and disposition and the contribution of genetic polymorphisms in these transport proteins to interindividual variability in the efficacy and safety for pharmacotherapy. This review summarizes the consequences of inherited differences in drug transport for pharmacotherapy. With the main focus on ABCB1, an update of recent advances is given and clinically relevant examples are used to illustrate how heritable differential drug transport can help to explain individual variability in drug response. The pharmacogenetics of other transporters is briefly introduced.

Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications

Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters, as well as drug metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.

Pharmacogenomics of MDR and MRP subfamilies.

Drug-metabolizing enzymes, drug transporters and drug targets play significant roles as determinants of drug efficacy and toxicity. Their genetic polymorphisms often affect the expression and function of their products and are expected to become surrogate markers to predict the response to drugs in individual patients. With the sequencing of the human genome, it has been estimated that approximately 500-1200 genes code for drug transporters and, recently, there have been significant and rapid advances in the research on the relationships between genetic polymorphisms of drug transporters and interindividual variation of drug disposition. At present, the clinical studies of multi-drug resistance protein 1 (MDR1, P-glycoprotein, ABCB1), which belongs to the ATP-binding cassette (ABC) superfamily, are the most comprehensive among the ABC transporters, but clinical investigations on other drug transporters are currently being performed around the world. MDR1 can be said to be the most important drug transporter, since clinical reports have suggested that it regulates the disposition of various types of clinically important drugs, but in vitro investigations or animal experiments have strongly suggested that the members of the multi-drug resistance-associated protein (MRP) subfamily can also become key molecules for pharmacotherapy. In addition to those, breast cancer resistance protein (BCRP, ABCG2), another ABC transporter, is well known as a key molecule of multi-drug resistance to several anticancer agents. However, this review focuses on the latest information on the pharmacogenetics of the MDR and MRP subfamilies, and its impact on pharmacotherapy is discussed.

Genetic Polymorphism of Organic Anion and Cation Transporters: Pharmacokinetic and Pharmacodynamic Consequences in Pharmacotherapy

It has been suggested that genetic polymorphisms in drug transporters as well as drug-metabolizing enzymes are associated with interindividual differences in drug disposition, efficacy, and toxicity and in disease. Organic anion and cation transporters are expressed in the selective or multiple tissues such as small intestine, liver and kidney, and mediate the transport of many clinically useful drugs. Polymorphisms of drug transporter genes have recently been identified and demonstrated to have functional significance for transporter activity and expression. For example, genetic variants in the OATP-C (SLC21A6) gene are associated with alterations in pravastatin and rifampin uptake into liver. In addition, homozygotes for OCTN2 (SLC22A5) mutant alleles cause systemic carnitine deficiency because of a disruption of carnitine reabsorption in the kidney. Since a growing number of preclinical and clinical studies have demonstrated that the polymorphisms of various drug transporter genes may be responsible for overall outcomes of pharmacokinetics and pharmacotherapy of certain drugs, further understanding of the physiology and biochemistry of drug transporters with respect to genetic variations will be important to establish individualized pharmacotherapy with clinically used drugs. Keywords: anion and cation transporters, genetic polymorphisms, clinically useful drugs, pharmacokinetics, pharmacodynamics