http://adaptivepharmacogenomics.com/ 2010-03-07T03:23:05Z Adaptive Pharmacogenomics, LLC esau.issaks@adaptivepharmacogenomics.com 2010-03-07T03:23:05Z PubMed:20204582

<p><b>Species differences in pharmacokinetics and pharmacodynamics.</b></p> <p>Handb Exp Pharmacol. 2010;199:19-48</p> <p>Authors: Toutain PL, Ferran A, Bousquet-Mélou A</p> <p>Veterinary medicine faces the unique challenge of having to treat many types of domestic animal species, including mammals, birds, and fishes. Moreover, these species have evolved into genetically unique breeds having certain distinguishable characteristics developed by artificial selection. The main challenge for veterinarians is not to select a drug but to determine, for the selected agent, a rational dosing regimen because the dosage regimen for a drug in a given species may depend on its anatomy, biochemistry, physiology, and behaviour as well as on the nature and causes of the condition requiring treatment. Both between- and within-species differences in drug response can be explained either by variations in drug pharmacokinetics (PK) or drug pharmacodynamics (PD), the magnitude of which varies from drug to drug. This chapter highlights selected aspects of species differences in PK and PD and considers underlying physiological and patho-physiological mechanisms in the main domestic species. Particular attention was paid to aspects of animal behaviour (food behaviour, social behavior, etc.) as a determinant of interspecies differences in PK or/and PD. Modalities of drug administration are many and result not only from anatomical, physiological and/or behavioural differences across species but also from management options. The latter is the case for collective/group treatment of food-producing animals, frequently dosed by the oral route at a herd or flock level. After drug administration, the main causes of observed inter-species differences arise from species differences in the handling of drugs (absorption, distribution, metabolism, and elimination). Such differences are most common and of greatest magnitude when functions which are phylogenetically divergent between species, such as digestive functions (ruminant vs. non-ruminant, carnivore vs. herbivore, etc.), are involved in drug absorption. Interspecies differences also exist in drug action but these are generally more limited, except when a particular targeted function has evolved, as is the case for reproductive physiology (mammals vs. birds vs. fishes; annual vs. seasonal reproductive cycle in mammals; etc.). In contrast, for antimicrobial and antiparasitic drugs, interspecies differences are more limited and rather reflect those of the pathogens than of the host. Interspecies difference in drug metabolism is a major factor accounting for species differences in PK and also in PD (production or not of active metabolites). Recent and future advances in molecular biology and pharmacogenetics will enable a more comprehensive view of interspecies differences and also between breeds with existing polymorphism. Finally, the main message of this review is that differences between species are not only numerous but also often unpredictable so that no generalisations are possible, even though for several drugs allometric approaches do allow some valuable interspecies extrapolations. Instead, each drug must be investigated on a species-by-species basis to guarantee its effective and safe use, thus ensuring the well-being of animals and safeguarding of the environment and human consumption of animal products.</p> <p>PMID: 20204582 [PubMed - in process]</p>

2010-03-04T03:23:05Z PubMed:19114346

<p>Nan Fang Yi Ke Da Xue Xue Bao. 2008 Dec;28(12):2161-4</p> <p>Authors: Fu SJ, Wang YB, Yu LX, Li Q, Wang YB, Xiao LL</p> <p>OBJECTIVE: To identify the factors responsible for the inter-individual variations in the dosage/concentration of tacrolimus in renal transplant recipients. METHODS: This study involved renal transplant recipients receiving immunosuppressive therapy with the tacrolimus, mycophenolate and prednisone regimen after the operation. The gender, age, height, body weight, tacrolimus dosage, hormone dosage, diarrhea, blood lipids, liver function, renal function, albumin, and hematocrit of the patients were recorded at different time points, namely in early stage (3, 7, 14, and 30 days postoperatively, 118 cases), at 3 months (103 cases), 6 months (75 cases) and over one year (119 cases) after the operation. The concentrations of tacrolimus and gene polymorphisms at CYP3A5, MDR1 3435, MDR1 2677 and MDR1 1236 were also determined in these patients. Multiple linear regression was used for analysis of these factors with tacrolimus concentration/dosage*body surface area as the independent variable. RESULTS: Patients in early stage following renal transplantation showed rather poor fitting of the stepwise regression model, which increased obviously 3 months after the operation and further increased till reaching a stable level at 6 months. Multiple factors were found to affect tacrolimus concentration/dosage in the early postoperative stage, during which period these factors underwent drastic variations and became stable 3 months later. In terms of pharmacogenomics, the major factors affecting tacrolimus concentration/dosage included MDR1 3435, MDR1 2677 and MDR1 1236 polymorphisms, which vastly varied between the patients early after the operation. Of these polymorphic sites, CYP3A5 produced only minor effects on tacrolimus concentration/dosage, and was not included as an active factor until the stable phase (over 1 year) following the transplantation; MDR1 3435 was found to be the predominant factor affecting tacrolimus metabolism in the stable phase. Age, liver function, albumin and hematocrit were found to be positively correlated to the independent variable tacrolimus concentration/dosage*body surface area, and identified as important factors responsible for the intra-individual variation of tacrolimus dosage/concentration. CONCLUSION: The variations in the factors affecting tacrolimus dosage/concentration after renal transplantation are consistent with the clinical features of the patients, and these factors vary with the postoperative stages. Pharmacogenomic factors produce the most conspicuous effect on tacrolimus dosage/concentration, and agents that may interfere with tacrolimus metabolism should be avoided after the operation. Age, liver function, albumin and hematocrit are also important factors responsible for the variation of tacrolimus dosage/concentration.</p> <p>PMID: 19114346 [PubMed - indexed for MEDLINE]</p>

2010-03-04T03:23:04Z PubMed:19442035

<p>Expert Opin Drug Metab Toxicol. 2009 Jul;5(7):745-55</p> <p>Authors: Hildebrandt MA, Gu J, Wu X</p> <p>NSCLC is the leading cause of cancer-related death in the US. Patients with NSCLC are mostly treated with platinum-based chemotherapy, often in combination with radiation therapy. However, the development of chemo-resistance is a major hurdle limiting treatment success. In this review, we summarize the current understanding of the genetic factors modulating chemoresistance to platinum chemotherapeutics and their association with clinical outcomes for NSCLC patients. We focus on candidate pathways responsible for drug influx and efflux, metabolism and detoxification, DNA damage repair, and other downstream cellular processes that modulate the effect of platinum-based therapy. We also discuss the application of pathway-based polygenic and genome-wide approaches in identifying genetic factors involved in NSCLC clinical outcomes. Overall, current studies have shown that the effects of each individual polymorphism on clinical outcomes are modest suggesting that a more comprehensive approach that incorporates polygenetic, phenotypic, epidemiologic and clinical variables will be necessary to predict prognosis for NSCLC patients receiving platinum-based chemotherapeutics.</p> <p>PMID: 19442035 [PubMed - indexed for MEDLINE]</p>

2010-03-04T03:23:04Z PubMed:20038765

<p>Neurology. 2010 Jan 5;74 Suppl 1:S62-9</p> <p>Authors: Pappas DJ, Oksenberg JR</p> <p>Genetic polymorphisms and variable expression of drug receptors, metabolizing enzymes, and transporters have been linked to interindividual differences in efficacy and toxicity of many Food and Drug Administration-approved therapeutic agents. In multiple sclerosis, the combination of heterogeneity of disease pathology and significant variation in clinical response to disease-modifying agents necessitates the definition of biomarkers that can a priori predict therapeutic response and define appropriate therapeutic regimens. Pharmacogenomic studies will directly address the question of heterogeneity by analysis of the correlation between different genomic variants and clinical responses to therapy. These studies will include longitudinal designs, maximize clinical response variables, include whole-genome technologies, use large patient cohorts, and require the development of novel mathematical algorithms designed to integrate the wealth of disparate data to identify modest genetic effects and interactions.</p> <p>PMID: 20038765 [PubMed - indexed for MEDLINE]</p>

2010-03-03T03:23:07Z PubMed:20041472

<p>Hum Psychopharmacol. 2010 Jan;25(1):84-91</p> <p>Authors: Al Hadithy AF, Ivanova SA, Pechlivanoglou P, Wilffert B, Semke A, Fedorenko O, Kornetova E, Ryadovaya L, Brouwers JR, Loonen AJ</p> <p>Neuronal degeneration due to oxidative stress (OS) has been proposed as a mechanism for tardive dyskinesia (TD) pathogenesis. Cellular defense mechanisms against OS may involve detoxification enzymes (e.g., glutathione peroxidase-1, GPX1; superoxide dismutase-2, SOD2 [also commonly known as MnSOD]; and glutathione S-transferase P1, GSTP1). Several pharmacogenetic studies have examined TD and OS in different ethnic groups, but not in Russians. Here we report the association between orofaciolingual (TDof) and limb-truncal dyskinesias (TDlt) and polymorphisms of GSTP1 (Ile105Val), MnSOD (Ala-9Val), and GPX1 (Pro197Leu) genes in 146 Russian inpatients from Siberia. We applied AIMS instrument to rate dyskinesias. Two-part model analyses, logistic and multivariate parametric regressions were applied to assess the effects of different variables (e.g., genotype, age, gender, and medication use). Our analyses do not suggest that Pro197Leu (GPX1) is associated with TD. However, our analyses suggest that the 105Val-allele of Ile105Val (GSTP1) may be associated with a lower risk and a severity of TDof and TDlt and that Ile105Val pharmacogenetics may be different in Slavonic Caucasians from that in American Caucasians. Furthermore, we find evidence for an association between Ala-9Val (MnSOD) and TDof, but not TDlt. Subject to further replication, our findings extend the available knowledge on the pharmacogenetics of TD and oxidative stress.</p> <p>PMID: 20041472 [PubMed - indexed for MEDLINE]</p>

2010-03-03T03:23:05Z PubMed:20017673

<p>Pharmacogenomics. 2010 Jan;11(1):65-79</p> <p>Authors: Alfirevic A, Alfirevic Z, Pirmohamed M</p> <p>The clinical application of pharmacogenetics has been well accepted by some medical specialties, but not all. The aim of this review is to discuss the current use of pharmacogenetics in reproductive and perinatal medicine and to highlight areas where pharmacogenetics may be able to help in the future to predict response to medicines in terms of efficacy and safety. This applies to drugs that are specific to pregnancy and reproduction, as well as drugs prescribed for the treatment of medical disorders in pregnancy. Our review points out the need for well-designed clinical studies on the efficacy and safety of medicines used in women of childbearing age in order to define the additional utility provided by pharmacogenetic testing.</p> <p>PMID: 20017673 [PubMed - indexed for MEDLINE]</p>

2010-03-03T03:23:05Z PubMed:20017675

<p>Pharmacogenomics. 2010 Jan;11(1):89-103</p> <p>Authors: Sissung TM, English BC, Venzon D, Figg WD, Deeken JF</p> <p>While no genome-wide pharmacogenetics study has yet been published, the field of pharmacogenetics is moving towards exploratory, large-scale analyses of the interaction between genetic variation and drug treatment. The Drug Metabolizing Enzymes and Transporters (DMET) platform offers a standardized set of 1936 variants in 225 genes related to drug absorption, distribution, metabolism and elimination that is useful to scan the genome for previously unknown associations between variation in absorption, distribution, metabolism and elimination genes and pharmacokinetic and pharmacodynamic outcomes of drug treatment. The purpose of this review is to put the DMET platform into context within the current study designs that have been used in pharmacogenetics, and to explore the role that DMET has played - and will play - in future pharmacogenetics studies.</p> <p>PMID: 20017675 [PubMed - indexed for MEDLINE]</p>

2010-03-03T03:23:05Z PubMed:20190862

<p><b>Pharmacogenetics and personal genomes.</b></p> <p>Per Med. 2009 Nov 1;6(6):643-652</p> <p>Authors: Wagner MJ</p> <p>While pharmacogenetics - the correlation of genotype and response to medicines - currently has a small but measurable impact on the prescribing practice of clinicians, the advent of the ;personal genome' is likely to change this significantly. Advances in high-throughput technologies aimed at characterizing human genetic variation, including chip-based genotyping and next-generation sequencing, are poised to provide a flood of information that will affect both pharmacogenetic discovery and pharmacogenetic application in clinical practice. In order for this flood of information to not overwhelm both researchers and clinicians alike, a variety of new and expanded information management tools will be needed, including electronic medical records, bioinformatic algorithms for analyzing sequence data, information management systems for storing, retrieving and interpreting whole-genome sequence data, and pharmacogenetic decision tools for prescribers.</p> <p>PMID: 20190862 [PubMed - as supplied by publisher]</p>

2010-03-03T03:23:05Z PubMed:20017668

<p>Pharmacogenomics. 2010 Jan;11(1):13-21</p> <p>Authors: Rakhra-Burris TK, Auman JT, Deverka P, Dressler LG, Evans JP, Goldberg RM, Havener TM, Hoskins JM, Jonas DE, Long KM, Motsinger-Reif AA, Irvin WJ, Richards KL, Roederer MW, Valgus JM, Riper M, Vernon JA, Zamboni WC, Wagner MJ, Walko CM, Weck KE, Wiltshire T, McLeod HL</p> <p>The Institute for Pharmacogenomics and Individualized Therapy (IPIT) at the University of North Carolina at Chapel Hill (NC, USA) is a collaborative, multidisciplinary unit that brings together faculty from different disciplines and crosses the traditional departmental/school structure to perform pharmacogenomics research. IPIT investigators work together towards the goal of developing therapies to enable the delivery of individualized medical care. The NIH-supported Comprehensive Research on Expressed Alleles in Therapeutic Evaluation (CREATE) group leads the field in the evaluation of pathways regulating drug activity, and also provides a foundation for future IPIT research. IPIT members perform bench research, clinical cohort analysis and prospective clinical intervention studies, research on the integration of pharmacogenomic therapy into practice and research to foster global health pharmacogenomics application through the Pharmacogenetics for Every Nation Initiative. IPIT Investigators are actively incorporating a pharmacogenomics curriculum into existing teaching programs at all levels.</p> <p>PMID: 20017668 [PubMed - indexed for MEDLINE]</p>

2010-03-03T03:23:05Z PubMed:20017669

<p>Pharmacogenomics. 2010 Jan;11(1):23-31</p> <p>Authors: Ciccacci C, Borgiani P, Ceffa S, Sirianni E, Marazzi MC, Altan AM, Paturzo G, Bramanti P, Novelli G, Palombi L</p> <p>Aims: Nevirapine is widely used to treat HIV-1 infection to prevent mother-to-child transmission; unfortunately adverse drug reactions have been reported. Our aim was to identify genes/variants involved in nevirapine-induced hepatotoxicity. MATERIALS &amp; METHODS: Patients from Mozambique, 78 with nevirapine-induced hepatotoxicity and 78 without adverse events, were genotyped for ABCB1, CYP2B6, CYP3A4 and CYP3A5 gene variants. We conducted a case-control association study and a genotype/phenotype correlation analysis. RESULTS: The ABCB1 c.3435C&gt;T SNP was associated with hepatotoxicity (p = 0.038), with the variant T allele showing a protective effect (odds ratio: 0.42). Moreover, four SNPs in the CYP2B6 and CYP3A5 genes resulted significantly correlated with transaminase values. In particular, for the CYP2B6 c.983T&gt;C SNP, the difference in the alanine aminotransferase mean values were highly significant between TT and TC genotypes (p &lt; 0.001). CONCLUSION: Our preliminary results confirm the contribution of the ABCB1 c.3435C&gt;T SNP in nevirapine-induced hepatotoxicity risk and, at the same time, suggest the necessity for further studies.</p> <p>PMID: 20017669 [PubMed - indexed for MEDLINE]</p>