11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/03/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/03/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/03/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Genetics of the patent ductus arteriosus (PDA) and pharmacogenetics of PDA treatment.

Semin Fetal Neonatal Med. 2018 Feb 24;:

Authors: Lewis TR, Shelton EL, Van Driest SL, Kannankeril PJ, Reese J

Abstract
Patent ductus arteriosus (PDA) is a frequent, complex, and difficult to treat clinical syndrome among preterm infants in the neonatal intensive care unit. In addition to known clinical risk factors, there are emerging data about genetic predisposition to PDA in both animal and human models. Clinical response and toxicity from drugs used to treat PDA are highly variable. Developmental and genetic aspects of pharmacokinetics and pharmacodynamics influence exposure and response to pharmacologic therapies. Given the variable efficacy and toxicity of known drug therapies, novel therapeutic targets for PDA treatment offer the promise of precision medicine. This review addresses the known genetic contributions to prolonged ductal patency, variability in response to drug therapy for PDA, and potential novel drug targets for future PDA treatment discovery.

PMID: 29510900 [PubMed - as supplied by publisher]

Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial.

Clin Lymphoma Myeloma Leuk. 2018 Feb 08;:

Authors: Rinaldetti S, Pfirrmann M, Manz K, Guilhot J, Dietz C, Panagiotidis P, Spiess B, Seifarth W, Fabarius A, Müller M, Pagoni M, Dimou M, Dengler J, Waller CF, Brümmendorf TH, Herbst R, Burchert A, Janβen C, Goebeler ME, Jost PJ, Hanzel S, Schafhausen P, Prange-Krex G, Illmer T, Janzen V, Klausmann M, Eckert R, Büschel G, Kiani A, Hofmann WK, Mahon FX, Saussele S

Abstract
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated.
MATERIALS AND METHODS: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated.
RESULTS: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (‰) was retained as the only significant variable (P = .02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P = .04). Patients with an ABCG2/GUSB transcript level >4.5‰ (n = 93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (≤4.5‰; n = 39) had a 12-month TFR rate of 72% (95% CI, 55%-82%).
CONCLUSION: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation.

PMID: 29510895 [PubMed - as supplied by publisher]

Pharmacogenetics of the anti-HCV drug sofosbuvir: a preliminary study.

J Antimicrob Chemother. 2018 Mar 02;:

Authors: Cusato J, De Nicolò A, Boglione L, Favata F, Ariaudo A, Mornese Pinna S, Carcieri C, Guido F, Avataneo V, Cariti G, Di Perri G, D'Avolio A

Abstract
Background: Sofosbuvir is a potent nucleotide HCV NS5B polymerase inhibitor that is also a P-glycoprotein (encoded by the ABCB1 gene) and breast cancer resistance protein (encoded by the ABCG2 gene) substrate. Concerning previous anti-HCV therapies, pharmacogenetics had a significant impact, particularly considering the association of interleukin28B polymorphisms with dual-therapy (ribavirin + pegylated IFN) outcomes.
Objectives: In this work, we investigated the association between sofosbuvir and its prevalent metabolite (GS-331007) plasma concentrations at 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCG2 and HNF4α) related to sofosbuvir transport.
Patients and methods: Allelic discrimination was performed through real-time PCR, whereas plasma concentrations were evaluated through liquid chromatography. One hundred and thirteen patients were enrolled.
Results: Sofosbuvir concentrations were below the limit of quantification since the drug was converted into its GS-331007 metabolite. ABCB1 2677 G>T (P = 0.044) and HNF4α 975 C>G (P = 0.049) SNPs were associated with GS-331007 metabolite plasma concentrations. In linear multivariate analysis, liver stiffness, insulin resistance, baseline haemoglobin and haematocrit and SNPs in the ABCB1 gene (3435 CT/TT and 1236 TT genotypes) were significant predictors of GS-331007 concentrations. Furthermore, we performed sub-analyses considering the anti-HCV concomitant drug and HCV genotype, identifying specific polymorphisms associated with GS-331007 plasma concentrations: ABCB1 3435 C>T and HNF4α975 C>G in patients treated with daclatasvir, ABCB1 2677 G>T with ledipasvir and ABCB1 3435 C>T, ABCB1 2677 G>T, ABCG2 421 C>A and ABCG2 1194 + 928 C>A with ribavirin.
Conclusions: In this study we suggested sofosbuvir GS-331007 metabolite plasma levels were affected by variants in the ABCB1 and HNFα genes.

PMID: 29509884 [PubMed - as supplied by publisher]

MSR1 repeats modulate gene expression and affect risk of breast and prostate cancer.

Ann Oncol. 2018 Mar 02;:

Authors: Rose AM, Krishan A, Chakarova CF, Moya L, Chambers S, Hollands M, Illingworth JC, Williams SMG, James HE, Shah AZ, Palmer CNA, Chakravarti A, Berg JN, Batra J, Bhattacharya SS

Abstract
Background: MSR1 repeats are a 36-38bp minisatellite element that have recently been implicated in the regulation of gene expression, through copy number variation (CNV).
Patients and methods: Bioinformatic and experimental methods were used to assess the distribution of MSR1 across the genome, evaluate the regulatory potential of such elements and explore the role of MSR1 elements in cancer, particularly non-familial breast cancer and prostate cancer.
Results: MSR1s are predominately located at chromosome 19 and are functionally enriched in regulatory regions of the genome, particularly regions implicated in short-range regulatory activities (H3K27ac, H3K4me1, and H3K4me3). MSR1-regulated genes were found to have specific molecular roles, such as serine-protease activity (P=4.80x10-7) and ion channel activity (P=2.7x10-4). The kallikrein locus was found to contain a large number of MSR1 clusters, and at least six of these showed CNV. An MSR1 cluster was identified within KLK14, with 9-copies and 11-copies being normal variants. A significant association with the 9-copy allele and non-familial breast cancer was found in two independent populations (P=0.004; P=0.03). In the white British population, the minor allele conferred an increased risk of 1.21 to 3.51-times for all non-familial disease, or 1.7 to 5.3-times in early-onset disease. The 9-copy allele was also found to be associated with increased risk of prostate cancer in an independent population (odds ratio = 1.27-1.56; P =0.009).
Conclusions: MSR1 repeats act as molecular switches that modulate gene expression. It is likely that CNV of MSR1 will affect risk of development of various forms of cancer, including that of breast and prostate. The MSR1 cluster at KLK14 represents the strongest risk factor identified to date in non-familial breast cancer and a significant risk factor for prostate cancer. Analysis of MSR1 genotype will allow development of precise stratification of disease risk and provide a novel target for therapeutic agents.

PMID: 29509840 [PubMed - as supplied by publisher]

PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC.

Br J Cancer. 2018 Mar 06;:

Authors: Del Re M, Marconcini R, Pasquini G, Rofi E, Vivaldi C, Bloise F, Restante G, Arrigoni E, Caparello C, Bianco MG, Crucitta S, Petrini I, Vasile E, Falcone A, Danesi R

Abstract
BACKGROUND: PD-L1 expression in tumour tissues is widely used to select patients to receive anti-PD-1/PD-L1 antibodies, but data are lacking on the correlation of plasma PD-L1 levels with the effect of treatments.
METHODS: To investigate the association between PD-L1 mRNA in plasma-derived exosomes and response to nivolumab and pembrolizumab in patients with melanoma (n=18) and NSCLC (n=8), blood was obtained at time point 0 and after 2 months. Exosomal PD-L1 mRNA was measured by digital droplet PCR.
RESULTS: The mean±s.e.m. PD-L1 levels in patients with complete and partial responses were 830.4±231.3 and 242.5±82.5 copies per ml at time 0 vs 2 months, respectively (P=0.016). In patients with stable disease the mean±s.e.m. values were 298.8±97.2 vs 247.5±29.8 copies per ml (P=0.586), while in progressive disease, PD-L1 mRNA levels were 204.0±68.8 vs 416.0±87.8 copies per ml at time 0 vs 2 months, respectively (P=0.001).
CONCLUSIONS: This study demonstrates that exosomal PD-L1 is significantly associated with response to treatment.British Journal of Cancer advance online publication, 6 March 2018; doi:10.1038/bjc.2018.9 www.bjcancer.com.

PMID: 29509748 [PubMed - as supplied by publisher]

Whole Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.

Am J Respir Crit Care Med. 2018 Mar 06;:

Authors: Mak AC, White MJ, Eckalbar WL, Szpiech ZA, Oh SS, Pino-Yanes M, Hu D, Goddard P, Huntsman S, Galanter J, Wu AC, Himes BE, Germer S, Vogel JM, Bunting KL, Eng C, Salazar S, Keys KL, Liberto J, Nuckton TJ, Nguyen TA, Torgerson DG, Kwok PY, Levin AM, Celedón JC, Forno E, Hakonarson H, Sleiman PM, Dahlin A, Tantisira KG, Weiss ST, Serebrisky D, Brigino-Buenaventura E, Farber HJ, Meade K, Lenoir MA, Avila PC, Sen S, Thyne SM, Rodriguez-Cintron W, Winkler CA, Moreno-Estrada A, Sandoval K, Rodriguez-Santana JR, Kumar R, Williams LK, Ahituv N, Ziv E, Seibold MA, Darnell RB, Zaitlen N, Hernandez RD, Burchard EG, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Abstract
Rationale Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. Objective To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. Methods We performed the first whole genome sequencing (WGS) pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. Measurements and Main Results We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (p < 3.53x10-7) and suggestive (p < 7.06x10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus (eQTL) for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and WGS data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings. Conclusion The lack of minority data, despite a collaboration of 8 universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

PMID: 29509491 [PubMed - as supplied by publisher]

Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients.

Oncotarget. 2018 Feb 06;9(10):9114-9136

Authors: Tecza K, Pamula-Pilat J, Lanuszewska J, Butkiewicz D, Grzybowska E

Abstract
The differences in patients' response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy. In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Selected genes and their polymorphisms were involved in FAC drugs transport (ABCB1, ABCC2, ABCG2,SLC22A16), metabolism (ALDH3A1, CBR1, CYP1B1, CYP2C19, DPYD, GSTM1, GSTP1, GSTT1, MTHFR,TYMS), DNA damage recognition, repair and cell cycle control (ATM, ERCC1, ERCC2, TP53, XRCC1). The multifactorial risk models that combine genetic risk modifiers and clinical characteristics were constructed for 12 toxic symptoms. The majority of toxicities was dependent on the modifications in components of more than one pathway of FAC drugs, while the impact level of clinical factors was comparable to the genetic ones. For the carriers of multiple high risk factors the chance of developing given symptom was significantly elevated which proved the factor-dosage effect. We found the strongest associations between concurrent presence of clinical factors - overall and recurrent anemia, nephrotoxicity and early nausea and genetic polymorphisms in genes responsible for DNA repair, drugs metabolism and transport pathways. These results indicate the possibility of selection of the patients with expected high tolerance to FAC treatment and consequently with high chance of chemotherapy completion without the dose reduction, treatment delays and decline in the quality of life.

PMID: 29507678 [PubMed]

Pharmacogenomics and drug therapy.

Aust Prescr. 2018 Feb;41(1):6

Authors: Goh S

PMID: 29507452 [PubMed]

Model-based Dosage Individualization of Ganciclovir in Neonates and Young Infants with Congenital Cytomegalovirus Infection: A Pilot Study.

Antimicrob Agents Chemother. 2018 Mar 05;:

Authors: Dong Q, Leroux S, Shi HY, Xu HY, Kou C, Khan MW, Jacqz-Aigrain E, Zhao W

Abstract
Background: Newborns with congenital cytomegalovirus (CMV) infection are at high risk for developing permanent sequelae. Intravenous ganciclovir therapy is frequently used for the treatment of congenital CMV infection. Target area under the concentration versus time curve (AUC0-24) of 40-50 μg·h/mL is recommended. The standard dose resulted in a large variability in ganciclovir exposure in newborns, indicating the unmet need of dosage individualization in this vulnerable population, but the implementation of this strategy remains challenging in clinical practice. We aim to evaluate the clinical utility of model-based dosage individualization of ganciclovir in newborns using an opportunistic sampling approach.Methods: The predictive performance of a published ganciclovir population pharmacokinetic model was evaluated using an independent patient cohort. The individual dose was adjusted based on the target AUC0-24 to ensure the efficacy.Results: A total of 26 newborns with congenital CMV infection were included in the present study. Only 11 (42.3%) patients achieved the target AUC0-24 after giving the standard dose. For all the subtherapeutic (below 80% target AUC) patients (n=5), model-based dosage adjustment was performed using Bayesian estimation method combined with the opportunistic sampling strategy. The adjusted doses were increased 28.6% - 60.0% in these five patients and all adapted AUC0-24 achieved the target (range: 48.6-66.1 μg·h/mL).Conclusion: The clinical utility of model-based dosing individualization of ganciclovir was demonstrated in newborns with congenital CMV infection. Population pharmacokinetic model combined with the opportunistic sampling strategy provides a clinical feasible method to adapt ganciclovir dose in neonatal clinical practice.

PMID: 29507070 [PubMed - as supplied by publisher]

Screening and identifying antioxidants from Oplopanax elatus using 2,2'-diphenyl-1-picrylhydrazyl with off-line two-dimensional HPLC coupled with diode array detection and tandem time-of-flight mass spectrometry.

J Sep Sci. 2016 Nov;39(22):4269-4280

Authors: Shao L, Nie MK, Chen MY, Wang J, Wang CZ, Huang WH, Yuan CS, Zhou HH

Abstract
The root of Oplopanax elatus (Nakai) Nakai has a well-known history of use for the treatment of diseases such as neurasthenia, cardiovascular disorders, and cancer by the native people in northeast China. It is important to screen and identify the bioactive molecules from its root rapidly. Hereby, an off-line two-dimensional high performance liquid chromatography coupled with diode array detection and tandem time-of-flight mass spectrometry together with 2,2'-diphenyl-1-picrylhydrazyl was established to screen antioxidants from the root of O. elatus. A Waters cyanogen column (150 × 3.9 mm, id, 4 μm) was used for the first dimensional liquid chromatography, while a Hypersil BDS-C18 column (250 × 4.6 mm, id, 5 μm) was installed for the second dimension liquid chromatographic analysis. Twenty-eight compounds had been tentatively identified from the methanol extract of the air-dried root of O. elatus including six polyynes and eight phenolic derivatives were screened with antioxidant activity. The developed method could be expedient for screening and identifying antioxidants from O. elatus.

PMID: 27624907 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/03/06

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/03/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Synthesis, structural and antimicrobial studies of type II topoisomerase-targeted copper(II) complexes of 1,3-disubstituted thiourea ligands.

J Inorg Biochem. 2018 Jan 16;182:61-70

Authors: Bielenica A, Drzewiecka-Antonik A, Rejmak P, Stefańska J, Koliński M, Kmiecik S, Lesyng B, Włodarczyk M, Pietrzyk P, Struga M

Abstract
A series of Cu(II) complexes of 3-(trifluoromethyl)phenylthiourea derivatives was synthesized. Their structural properties were investigated by spectroscopic techniques (infrared and electron paramagnetic resonance), as well as molecular modeling. All studied coordination compounds are mononuclear complexes containing two chelating ligands bonded to the metal cation via S and deprotonated N atoms. The new chelates were evaluated for their antimicrobial potency. The complex of 1-(3,4-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea (3) presented the highest activity against Gram-positive pathogens, even stronger than the activity of its non-complexed counterpart and the reference drug. The compound also prevented the biofilm formation of methicillin-resistant and standard strains of staphylococcal cocci. The title derivatives were found to be effective inhibitors of DNA gyrase and topoisomerase IV isolated from Staphylococcus aureus. The binding modes of the ligand L3 with DNA gyrase and topoisomerase IV were presented.

PMID: 29499458 [PubMed - as supplied by publisher]

Precision medicine in diabetes prevention, classification and management.

J Diabetes Investig. 2018 Mar 02;:

Authors: Xie F, Chan JCN, Ma RCW

Abstract
Diabetes has become a major burden of healthcare expenditure. Diabetes management following a uniform treatment algorithm is often associated with progressive treatment failure and development of diabetic complications. Recent advances in our understanding in the genomic architecture of diabetes and its complications have provided the framework for development of precision medicine to personalize diabetes prevention and management. In this review, we summarized recent advances in the understanding of the genetic basis of diabetes and its complications. From a clinician's perspective, we attempted to provide a balanced perspective on the utility of genomic medicine in the field of diabetes. Using genetic information to guide management of monogenic forms of diabetes represents the best-known examples of genomic medicine for diabetes. While major strides have been made in genetic research for diabetes, its complications and pharmacogenetics, ongoing efforts are needed to translate these findings into practice by incorporating genetic information into risk prediction model for prioritization of treatment strategies as well as using multi-omic analysis to discover novel drug targets with companion diagnostics. Further research is also needed to ensure appropriate use of these information to empower individuals and healthcare professionals to make personalized decision for achieving optimal outcome. This article is protected by copyright. All rights reserved.

PMID: 29499103 [PubMed - as supplied by publisher]

Pharmacogenomics and the Placebo Response.

ACS Chem Neurosci. 2018 Mar 02;:

Authors: Hall KT, Loscalzo J, Kaptchuk T

Abstract
There is perhaps no more important time in the history of placebos to consider their role in clinical trials and in medicine. Increasingly well-designed pharmaceutical and academic clinical trials testing promising and established drug and surgical interventions have failed to "beat" the placebo response. The collateral damage resulting from these failures is staggering; novel treatments, many with compelling mechanisms of action and promising Phase 2 trial results, never reach the patient, adversely affecting small and large pharma alike. Recent evidence suggests that variability in placebo response may be attributed in part to genetic variation. Thus, having a better understanding of the genomic underpinnings of the placebo response, the "placebome", may pave the way to innovatively and more effectively use placebos in drug development.

PMID: 29498823 [PubMed - as supplied by publisher]

Pharmacogenetics of Dopamine β-Hydroxylase in cocaine dependence therapy with doxazosin.

Addict Biol. 2018 Mar 02;:

Authors: Zhang X, Nielsen DA, Domingo CB, Shorter DI, Nielsen EM, Kosten TR

Abstract
The α1 -adrenergic antagonist, doxazosin, has improved cocaine use disorder (CUD) presumably by blocking norepinephrine (NE) stimulation and reward from cocaine-induced NE increases. If the NE levels for release were lower, then doxazosin might more readily block this NE stimulation and be more effective. The NE available for release can be lower through a genetic polymorphism in dopamine β-hydroxylase (DBH) (C-1021T, rs1611115), which reduces DβH's conversion of dopamine to NE. We hypothesize that doxazosin would be more effective in CUD patients who have these genetically lower DβH levels. This 12-week, double-blind, randomized, placebo-controlled trial included 76 CUD patients: 49 with higher DβH levels from the DBH CC genotype and 27 with lower DβH levels from T-allele carriers (CT or TT). Patients were randomized to doxazosin (8 mg/day, N = 47) or placebo (N = 29) and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy. Cocaine use was reduced at a higher rate among patients in the doxazosin than in the placebo arm. We found significantly lower cocaine use rates among patients carrying the T-allele (CT/TT) than the CC genotype. The percentage of cocaine positive urines was reduced by 41 percent from baseline in the CT/TT group with low DβH and NE levels, as compared with no net reduction in the CC genotype group with normal DβH and NE levels. The DBH polymorphism appears play an important role in CUD patients' response to doxazosin treatment, supporting a pharmacogenetic association and potential application for personalized medicine.

PMID: 29498170 [PubMed - as supplied by publisher]

Navigating Transporter Sciences in Pharmacokinetics Characterization Using Extended Clearance Classification System (ECCS).

Drug Metab Dispos. 2018 Mar 01;:

Authors: El-Kattan AF, Varma MVS

Abstract
Membrane transporters play an important role in the absorption, distribution, clearance and elimination (ADCE) of the drugs. Supported by the pharmacokinetics data in human, several transporters including organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion proteins (MATEs), P-glycoprotein and breast cancer resistance protein (BCRP) are suggested to be of clinical relevance. An early understanding of transporters role in the drug disposition and clearance allows reliable prediction/evaluation of the pharmacokinetic changes due to drug-drug interactions (DDIs) or genetic polymorphisms. We recently proposed extended clearance classification system (ECCS) based on simple drug properties (i.e., ionization permeability and molecular weight) to predict predominant clearance mechanism. According to this framework, systemic clearance of class 1B and 3B drugs is likely determined by the OATP-mediated hepatic uptake. Class 3A, 4 and certain class 3B drugs are predominantly cleared by renal, wherein, OAT1, OAT3, OCT2 and MATEs could contribute to their active renal secretion. Intestinal efflux and uptake transporters largely influence the oral pharmacokinetics of class 3A, 3B and 4 drugs. We discuss the paradigm of applying ECCS framework in mapping the role of clinically relevant drug transporters in early discovery and development; and thereby, implementing the right strategy to allow optimization of drug exposure and evaluation of clinical risk due to DDIs and pharmacogenomics.

PMID: 29496721 [PubMed - as supplied by publisher]