Polymorphism In Drug Metabolism Research Articles

Cyclophosphamide and 4‐hydroxycyclophosphamide pharmacokinetics in patients with glomerulonephritis secondary to lupus and small vessel vasculitis

Cyclophosphamide, the precursor to the active 4-hydroxycyclophosphamide, is used in active glomerulonephritis despite limited pharmacokinetics data. The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide were evaluated. The influence of laboratory and pharmacogenomic covariates on pharmacokinetics was evaluated as a secondary aim. Glomerulonephritis patients (n = 23) participated in a pharmacokinetic evaluation. Blood was serially collected and assayed for cyclophosphamide and 4-hydroxycyclophosphamide by LC/MS methods. Kidney function, serum albumin and polymorphisms in drug metabolism or transport genes were evaluated. Analyses included non-compartmental pharmacokinetics and parametric and non-parametric statistics. The mean area under the plasma concentration-time curve (AUC(0,∞)) data were 110,100 ± 42,900 ng ml(-1) h and 5388 ± 2841 ng ml(-1) h for cyclophosphamide and 4-hydroxycyclophosphamide, respectively. The mean metabolic ratio was 0.06 ± 0.04. A statistically significant relationship was found between increased serum albumin and increased half-life (0.584, P = 0.007, 95% CI 0.176, 0.820) and a borderline relationship with AUC(0,∞) (0.402, P = 0.079, 95% CI -0.064, 0.724) for 4-hydroxycyclophosphamide. Covariate relationships that trended toward significance for cyclophosphamide included decreased serum albumin and increased elimination rate constant (-0.427, P = 0.061, 95% CI 0.738, 0.034), increased urinary protein excretion and increased AUC(0,∞) (-0.392, P = 0.064, 95% CI -0.699 to 0.037), decreased C(max) (0.367, P = 0.085, 95% CI -0.067, 0.684) and decreased plasma clearance (-0.392, P = 0.064, 95% CI -0.699, 0.037). CYP2B6*9 variants vs. wildtype were found to have decreased elimination rate constant (P = 0.0005, 95% CI 0.033, 0.103), increased V(d) (P = 0.0271, 95% CI -57.5, -4.2) and decreased C(max) (P = 0.0176, 95% CI 0.696, 6179) for cyclophosphamide. ABCB1 C3435T variants had a borderline decrease in cyclophosphamide elimination rate constant (P = 0.0858; 95% CI -0.005, 0.102). Pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in patients with lupus nephritis and small vessel vasculitis are similar. Clinical and pharmacogenetic covariates alter disposition of cyclophosphamide and 4-hydroxycyclophosphamide. Clinical findings of worsened glomerulonephritis lead to increased exposure to cyclophosphamide vs. the active 4-hydroxycyclophosphamide, which could have relevance in terms of clinical efficacy. The CYP2B6*9 and ABCB1 C3435T polymorphisms alter the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in glomerulonephritis.

Interrogation of polymorphisms in drug metabolism or transport genes and peripheral neuropathy during paclitaxel treatment.

10515 Background: Peripheral neuropathy is the most common severe toxicity in patients treated with paclitaxel. Putative genetic mutations in genes relevant to drug metabolism, distribution, and elimination may explain the differences in risk of neurotoxicity among patients. Using a genotyping platform that interrogates nearly 2,000 known variants in drug exposure genes, we hypothesized that polymorphisms could be identified which modulate a patient’s risk of neuropathy during paclitaxel treatment. Methods: Subjects included in this study were treated for breast cancer with paclitaxel-containing regimens. Clinical data, including patient characteristics and toxicity, was collected prospectively in an observational registry. Blood was collected at diagnosis and genotyped using the Affymetrix DMET Plus chip at Gentris. The primary endpoint was grade 2+ neuropathy as defined by NCI CTC criteria. Statistical analysis was carried out using Fisher’s exact test for each SNP, without assumption of a specific genetic model. For this hypothesis-generating study, a p-value of <0.001 was selected for significance. Results: 412 breast cancer patients treated with paclitaxel were included in the analysis. The median age was 50, 107 (26%) were African-American, and 48 (12%) had preexisting diabetes. The prevalence of grade 2+ neuropathy was 18.5% in the cohort. After exclusion of SNPs based on call rate, Hardy-Weinberg equilibrium, and allele frequency, 564 SNPs were interrogated for an association with grade 2+ neuropathy. Two SNPs, rs3788007 (ABCG1_43706676G>A[Intron]) and rs6163 (CYP17A1_195G>T[S65S]), were associated with grade 2+ neurotoxicity p=0.0003 (OR=3.54, 95% CI: 1.77-7.72) and p=0.0008 (OR=0.35, 95%CI: 0.18-0.66), respectively. Conclusions: We identified two SNPs, both in genes not previously investigated in paclitaxel pharmacogenetic studies, which were associated with modified risk of paclitaxel-induced neuropathy. Both genes are implicated in endogenous steroid biology, which is thought to be relevant to neuropathy development, and one SNP (rs6163) is in high LD (r2=0.93) with a SNP recently reported to be associated with bortezomib-induced neuropathy.

Infectious Disease Management through Point-of-Care Personalized Medicine Molecular Diagnostic Technologies.

Infectious disease management essentially consists in identifying the microbial cause(s) of an infection, initiating if necessary antimicrobial therapy against microbes, and controlling host reactions to infection. In clinical microbiology, the turnaround time of the diagnostic cycle (>24 hours) often leads to unnecessary suffering and deaths; approaches to relieve this burden include rapid diagnostic procedures and more efficient transmission or interpretation of molecular microbiology results. Although rapid nucleic acid-based diagnostic testing has demonstrated that it can impact on the transmission of hospital-acquired infections, we believe that such life-saving procedures should be performed closer to the patient, in dedicated 24/7 laboratories of healthcare institutions, or ideally at point of care. While personalized medicine generally aims at interrogating the genomic information of a patient, drug metabolism polymorphisms, for example, to guide drug choice and dosage, personalized medicine concepts are applicable in infectious diseases for the (rapid) identification of a disease-causing microbe and determination of its antimicrobial resistance profile, to guide an appropriate antimicrobial treatment for the proper management of the patient. The implementation of point-of-care testing for infectious diseases will require acceptance by medical authorities, new technological and communication platforms, as well as reimbursement practices such that time- and life-saving procedures become available to the largest number of patients.

Susceptibility of Human Lymphocytes to 2-Nitrofluorene-Induced Gene Mutation is Strongly Dependent on Metabolic Genotypes

Genetic polymorphisms in drug metabolism contribute largely to adverse drug reactions in susceptible individuals due to excess production of reactive metabolites and active oxygen species. We conducted an in vitro study that clearly demonstrates that functional impact of common polymorphisms in the metabolic genes, such as N-acetyltransferase 2 (NAT2), can be easily reflected in mutant induction in the gene coding for hypoxanthineguanine phosphoribosyl transferase (HPRT) in T-lymphocytes isolated from human peripheral blood. NAT2 is involved in the metabolic activation of 2-nitrofluorene (2-NF) to the known aromatic amide carcinogen N-acetyl- 2-aminofluorene. Subsequent deactivation through glutathione conjugation involves glutathione S-transferase M1 (GSTM1). We obtained a clear dose-related increase in the HPRT mutant frequency after treating mitogen-stimulated lymphocytes isolated from a normal blood donor with 2-NF (up to 5 fold at 400 μg/mL, 24h exposure), while no HPRT mutant induction was observed using cells from another blood donor. The susceptible cells turned out to have the NAT2 rapid and GSTM1 null genotype combination (capable of activation, with insufficient deactivation), while the resistant cells had the NAT2 slow and GSTM1 positive combination. Although the contribution of GSTM1 genotype is less clear, our finding suggests that functional polymorphisms in key metabolic genes do affect induction of gene mutations at the HPRT locus and at least the NAT2 genotype plays a critical role in determining the susceptibility of human cells to genotoxicity of 2-NF. Further, human peripheral T-lymphocytes and the in vitro HPRT gene mutation assay can be utilized to study the functional impact of common genetic polymorphisms in drug metabolism and to identify risk genotypes susceptible for drug toxicity and somatic mutations.

Next level of immunosuppression: Drug/immune monitoring

1. Current immunological monitoring relies heavily on clinical judgment and therapeutic drug levels and does not adequately assess the functional or donor-specific immunosuppression (IS) status of recipients of liver transplantation (LT). 2. Trough levels of drugs are arbitrary and are more clinically relevant for preventing supratherapeutic or subtherapeutic dosing and blood concentrations and for more closely monitoring at-risk populations (children, the elderly, and patients with organ dysfunction). The AUC or the post-dose levels may be more precise, but they have not been used extensively by transplant centers. 3. Data on drug/immune monitoring specific to LT are fairly limited; therefore, clinical practice is often borrowed from experiences with nonhepatic transplantation (mainly renal transplantation). 4. The monitoring of drug levels in patients taking generic immunosuppressants is challenging because the formulations may change with each prescription. The monitoring of drug or antibody levels is not yet clinically available for biological therapies (induction, lymphocyte-depleting, and maintenance agents). 5. Polymorphisms in drug metabolism (cytochrome P450 and P-glycoprotein) may be useful in selecting the initial and maintenance dosages of immunosuppressants and in preventing complications from over or underimmunosuppression. 6. Future immune monitoring assays should be focused on genomic or immunological predispositions and on specific reactivities to donor antigens to guide the appropriate dosing and minimization of IS after LT.

Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent

Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults. We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated severe (grade III/IV) cutaneous and/or hepatic adverse events within 8 weeks of initiating nevirapine. Controls did not experience adverse events during more than 18 weeks of nevirapine therapy. Cases and controls were matched 1: 2 on baseline CD4 T-cell count, sex, and race. Individuals with 150 or less CD4 T cells/μl at baseline were excluded. We characterized 123 human leukocyte antigen (HLA) alleles and 2744 single-nucleotide polymorphisms in major histocompatibility complex (MHC) and drug metabolism and transport genes. We studied 276 evaluable cases (175 cutaneous adverse events, 101 hepatic adverse events) and 587 controls. Cutaneous adverse events were associated with CYP2B6 516G→T (OR 1.66, all), HLA-Cw*04 (OR 2.51, all), and HLA-B*35 (OR 3.47, Asians; 5.65, Thais). Risk for cutaneous adverse events was particularly high among Blacks with CYP2B6 516TT and HLA-Cw*04 (OR 18.90) and Asians with HLA-B*35 and HLA-Cw*04 (OR 18.34). Hepatic adverse events were associated with HLA-DRB*01 (OR 3.02, Whites), but not CYP2B6 genotypes. Associations differed by population, at least in part reflecting allele frequencies. Among patients with at least 150 CD4 T cells/μl, polymorphisms in drug metabolism and immune response pathways were associated with greater likelihood of risk for nevirapine-related adverse events. Results suggest fundamentally different mechanisms of adverse events: cutaneous, most likely MHC class I-mediated, influenced by nevirapine CYP2B6 metabolism; hepatic, most likely MHC class II-mediated and unaffected by such metabolism. These risk variants are insensitive for routine clinical screening.

High-resolution melting curve analysis to establish CYP2C19∗2 single nucleotide polymorphism: Comparison with hydrolysis SNP analysis

Clinically significant consequences of CYP2C19 polymorphism in drug metabolism require reliable genotyping methods for assaying large numbers of blood samples. Hydrolysis single nucleotide polymorphism analysis and high-resolution melting curve (HRM) analysis successfully genotyped the 114 liver donors for CYP2C19∗2. However, the HRM analysis was found to be more efficient, rapid, user- and cost-friendly method.

Review: Pharmacogenetic aspects of the effect of cytochrome P450 polymorphisms on serotonergic drug metabolism, response, interactions, and adverse effects

The field of pharmacogenetics contains a wealth of potential for the enhancement of clinical practice by providing a more effective match between patient and drug, consequently reducing the probability of an adverse drug reaction. Although a relatively novel concept in the forensic context, pharmacogenetics has the capability to assist in the interpretation of drug related deaths, particularly in unintentional drug poisonings where the cause of death remains unclear. However, the complex pharmacology of the drugs when subjected to genetic variations in metabolism makes interpretation of the expected response and adverse events difficult. Many possess multiple metabolic pathways, narrow therapeutic indices and active metabolites or enantiomers which may be eliminated via different pathways to the parent drug. A number of these drugs, which are metabolised primarily by the CYP450 system, are also associated with serotonin syndrome, or serotonin toxicity, especially when used concomitantly with other serotonin active drugs which rely on the same metabolic pathways for drug elimination. A comprehensive understanding of polymorphic drug metabolism and its expected outcomes is therefore essential when interpreting the involvement of drugs in adverse reactions. This review examines the genetically variable CYP450-mediated metabolism of a number of serotonin-active drugs that are often implicated in cases of serotonin toxicity, to assess the impact of pharmacogenetics on drug metabolism, response, interactions and adverse effects.

A huge number of mixtures and substances: How to deal with them?

It is of great importance that the effects of any potentially interacting factors, such as food supplements, nutraceuticals, and dietary products, folk herbal and medicinal plants with general chemotherapy are identified and assessed. A survey of the main molecules from such products available need to be assessed to help in the understanding of the possible risk involved.Nevertheless in all these products a huge number of mixtures and substances are present, the more suggested situations in literature which cause herbal–drug interactions, are regarding both phases of the metabolizing process. Phase-I (functionalization, mainly involving CYP450 iso-enzymes as 2C6 and 3A4) and Phase-II (conjugation, mainly sulpho- and glucuron-) reactions are the more important.Variable factors such as age-dependent variations and changes caused by physiological conditions and diseases, as well as on drug–drug, food–drug or herbal–drug interactions may lead to variations in drug metabolism. Diversity in the genome is the main source for differences in drug metabolism between animal species including humans and leads to variations between individuals of a particular species. A broad range of relevant polymorphic enzymes and examples of affected drugs are published. A profound knowledge on frequent variations in drug metabolizing enzymes and their consequences is indispensable for personalized pharmacotherapy (Kramer and Testa, 2008). In a near future approaches for therapy optimization with regard to genetic polymorphisms in drug metabolism will be available.In mean time it is important to have the most reports possible in this issue that will help us to understand this complex mechanism and create easy ways to help the patients and the knowledge to educate the population in general with the warnings that need to be proven for future advice.

Polymorphic Drug Metabolism in Anaesthesia

A substantial part of the interindividual variability in response to drugs and xenobiotics is related to genetically-determined impairment in drug metabolism. Several drug-metabolising enzymes are polymorphic in humans and often polymorphisms are strongly related to altered drug biodisposition and to the risk of developing adverse effects. Drugs used in general anaesthesia undergo polymorphic metabolism. Among these, halothane is metabolized by cytochrome P450 (CYP) 2E1 and, to a lesser extent, by CYP3A4 and CYP2A6. CYP2E1 also plays a key role in the metabolism of isoflurane, sevoflurane, enflurane and desflurane. CYP2B6, CYP3A4 and CYP2C9 play a relevant role in the metabolism of ketamine. The enzymes involved in the metabolism of thiopental and etomidate remains to be elucidated. Propofol is metabolized mainly by glucuronidation by uridine diphosphate-glucuronosyltransferases (UGTs) and by hydroxylation by CYP2B6 and CYP2C enzymes. The enzymes SULT1A1 and NQO1 participate in later steps in propofol metabolism. All the above-mentioned anaesthetic-metabolising enzymes are polymorphic in man. The present review analyzes the importance of enzymes in the metabolism of anaesthetics and common polymorphisms related to the biotransformation of general anaesthetics and it raises hypotheses on genetic and non-genetics factors related to altered response to anaesthetics that require further investigation. Based on functional relevance and allele frequencies, we identify the most promising targets for the clinical use of pharmacogenomic techniques in anaesthesia to prevent altered pharmacokinetics or adverse drug effects.

No association between HLA-B and cutaneous reactions to sulphonamides in human immunodeficiency virus-infected patients

Conflicts of interest: none declared. Sir, Sulphonamides are commonly used antibiotic drugs. The sulphonamide family includes drugs used to treat the most common opportunistic infections in patients with AIDS. Their use is complicated by the unusually high rate of cutaneous drug reactions (CDR).1 The frequency of CDR to sulphonamides is approximately 5% in the general population and 10 times greater in human immunodeficiency virus (HIV)‐infected patients.2 Increasing evidence shows that CDR are genetically determined. Most of the studied polymorphisms in drug metabolism are not risk factors for sulphamide reactions.3, 4 More recent studies focusing on immunological rather than metabolic factors have demonstrated the involvement of HLA markers in the susceptibility to hypersensitive reactions to abacavir and nevirapine.5, 6 In this study, associations between HLA polymorphisms and CDR to sulphonamides were explored in the Epitox cohort of patients with AIDS. From 1995 to 1997, 136 HIV‐infected patients treated with sulfamethoxazole/trimethoprim for Pneumocystis carinii pneumonia or with sulfadiazine for cerebral toxoplasmosis were prospectively included in the study and followed up for 30 days. Patients with CDR to sulphonamides during this period were compared with patients without CDR. Participants were included according to the French laws governing participation in biomedical research and with approval of the local Ethics Committee. Each participant provided informed consent. The elapsed time between the initial Epitox study and this new genotyping study is due to a new hypothesis about the involvement of HLA in the susceptibility to CDR.5, 6 The Epitox cohort of patients with AIDS was used to evaluate HLA‐B polymorphism as a risk factor for CDR to sulphonamides. The number of patients genotyped for HLA‐B was limited by DNA quantity and quality. This subgroup of patients was not different from the entire cohort for its main characteristics. Twenty‐two individuals had developed CDR and 26 individuals did not show evidence of CDR to sulphonamides. All patients and controls were typed for HLA‐B locus. Low‐resolution HLA‐B genotyping was performed by polymerase chain reaction with sequence‐specific primers (GenoVision; Qiagen, Valencia, CA, U.S.A.).

MDR1 and CYP3A4 Polymorphisms Are Associated with HIV Seropositivity in Israeli Patients But Do Not Influence the Course of HIV Disease

Recent studies have examined the relationship between polymorphic alleles of the MDR1 gene and the course of HIV. Such polymorphisms may alter the metabolism of antiretroviral medications or influence susceptibility to HIV infectivity. We therefore studied a polymorphism in MDR1 (C3435T), and the CYP3A4*1B variant allele, the latter of which has not been previously studied in HIV. Ninety-six patients of either Ethiopian (57) or Caucasian (39) ethnicity and 276 controls were studied including serial CD4 counts, clinical course, and AIDS-defining illnesses. For both ethnic groups, the C allele of MDR1 C3435T was highly associated with being infected with HIV (p < 0.0001) compared to controls, but genotype did not influence change in CD4 counts over time in the patients, whether or not they were treated with antiretrovirals. CYP3A4*1B was also significantly associated with being infected with HIV (p < 0.0001) both in heterozygotes and in homozygotes for the polymorphism, but only for Ethiopians (p < 0.023 compared to Caucasians, p = 0.44). CYP3A4*1B did not influence CD4 count or AIDS defining illnesses. We conclude that in Israeli patients, polymorphisms in drug metabolism and disposition genes may influence infectivity of HIV but do not influence the course of the disease. Larger studies are needed to confirm these findings.

Involvement of Multiple Cytochrome P450 and UDP-Glucuronosyltransferase Enzymes in the in Vitro Metabolism of Muraglitazar

Muraglitazar (Pargluva), a dual alpha/gamma peroxisome proliferator-activated receptor activator, has both glucose- and lipid-lowering effects in animal models and in patients with diabetes. The human major primary metabolic pathways of muraglitazar include acylglucuronidation, aliphatic/aryl hydroxylation, and O-demethylation. This study describes the identification of human cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) enzymes involved in the in vitro metabolism of muraglitazar. [(14)C]Muraglitazar was metabolized by cDNA-expressed CYP2C8, 2C9, 2C19, 2D6, and 3A4, but to a very minimal extent by CYP1A2, 2A6, 2B6, 2C18, 2E1, and 3A5. Inhibition of the in vitro metabolism of muraglitazar in human liver microsomes, at a clinically efficacious concentration, by chemical inhibitors and monoclonal antibodies further supported involvement of CYP2C8, 2C9, 2C19, 2D6, and 3A4 in its oxidation. A combination of intrinsic clearance (V(max)/K(m)) and relative concentrations of each P450 enzyme in the human liver was used to predict the contribution of CYP2C8, 2C9, 2C19, 2D6, and 3A4 to the formation of each primary oxidative metabolite and to the overall oxidative metabolism of muraglitazar. Glucuronidation of [(14)C]muraglitazar was catalyzed by cDNA-expressed UGT1A1, 1A3, and 1A9, but not by UGT1A6, 1A8, 1A10, 2B4, 2B7, and 2B15. The K(m) values for muraglitazar glucuronidation by the three active UGT enzymes were similar (2-4 muM). In summary, muraglitazar was metabolized by multiple P450 and UGT enzymes to form multiple metabolites. This characteristic predicts a low potential for the alteration of the pharmacokinetic parameters of muraglitazar via polymorphic drug metabolism enzymes responsible for clearance of the compound or by coadministration of drugs that inhibit or induce relevant metabolic enzymes.

AmpliChip for Cytochrome P-450 Genotyping: The Epoch of Personalized Prescriptions

The clinical importance of genetic polymorphisms in drug metabolism is well-known in clinical pharmacotherapy. The first widely available pharmacogenomic microarray technology approved by the Food and Drug Administration as a medical device to clinically genotype genetic polymorphisms in drug metabolism is now available with the launch of AmpliChip technology. This readily accessible clinical microarray test allows the genotyping of cytochrome (CYP) P-450 2D6 and 2C19 and marks a milestone in the epoch of evidence based personalized medicine. Many commonly used drugs are substrates for CYP2D6 and CYP 2C19 and hence may potentially demonstrate phenotypic differences as poor, intermediate, extensive, and ultrarapid metabolizers. These phenotypic variations could lead to expressed differences in pharmacotherapeutic patient outcomes. AmpliChip currently allows for testing of multiple alleles (31) in a single assay. Other technologies for pharmacogenomics are on the horizon. This article reviews the importance of polymorphic enzymes and genotyping as to how genetic polymorphisms alter pharmacotherapy and the emergence of a plethora of technologies that may become routinely available for clinical pharmacogenomic testing in the near future.

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

Many marketed drugs are chiral and are administered as the racemate, a 50:50 combination of two enantiomers. Pharmacodynamic and pharmacokinetic differences between enantiomers are well documented. Because of enantioselectivity in pharmacokinetics, results of in vitro pharmacodynamic studies involving enantiomers may differ from those in vivo where pharmacokinetic processes will proceed. With respect to pharmacokinetics, disparate plasma concentration vs time curves of enantiomers may result from the pharmacokinetic processes proceeding at different rates for the two enantiomers. At their foundation, pharmacokinetic processes may be enantioselective at the levels of drug absorption, distribution, metabolism and excretion. In some circumstances, one enantiomer can be chemically or biochemically inverted to its antipode in a unidirectional or bidirectional manner. Genetic consideration such as polymorphic drug metabolism and gender, and patient factors such as age, disease state and concomitant drug intake can all play a role in determining the relative plasma concentrations of the enantiomers of a racemic drug. The use of a nonstereoselective assay method for a racemic compound can lead to difficulties in interpretation of data from, for example, bioequivalence or dose/concentration vs effect assessments. In this review data from a number of representative studies involving pharmacokinetics of chiral drugs are presented and discussed.

Global systems biology, personalized medicine and molecular epidemiology

Mol Syst Biol. 2: 52 One of the great challenges for 21st century medicine is to deliver effective therapies that are tailored to the exact biology or biological state of an individual to enable so‐called ‘personalized healthcare solutions’. Ideally, this would involve a system of patient evaluation that would tell clinicians the correct drug, dose or intervention for any individual before the start of therapy. A practical approach to this evaluation is the concept of patient stratification in which individuals are biologically subclassified (classically according to some genetic features) and biofeatures modelled in relation to outcome. In principle, such stratification for personalized therapy can be applied to drug safety and efficacy modelling and to more general healthcare paradigms involving optimized nutrition and lifestyle management. Of course, truly personalized treatments, even if they can be developed and applied widely, will lamentably always be a luxury of the worlds' richest citizens and nations. So in some respects, personalized healthcare might appear to be at the opposite end of the medical spectrum to the subject of epidemiology in which disease risk factors and disease incidence are studied in populations rich and poor alike. Systems biology provides us with a common language for both describing and modelling the integrated action of regulatory networks at many levels of biological organization from the subcellular through cell, tissue and organ right up to the whole organism. The relatively new science of molecular epidemiology concerns the measurement of the fundamental biochemical factors that underlie population disease demography and understanding ‘the health of nations’ and this subject naturally lends it to systems biology approaches. Hence, systems biology is certain to have in future a major role in both the development of personalized medicine and in molecular epidemiological studies. Populations are, of course, made up of individuals and, in …

Dextromethorphan metabolic phenotyping in an Iranian population

CYP2D6 polymorphism of drug metabolism represents an important source of interindividual and interethnic variation in drug response. Since this polymorphism has not been studied in an Iranian population, the present study was undertaken. Two hundred healthy unrelated Iranian subjects participated in this study. Phenotyping was based on high-performance liquid chromatography determination of the dextromethorphan/total dextrorphan molar ratios as metabolic ratios (MRs) in plasma samples collected at 3 h after oral administration of 30 mg dextromethorphan hydrobromide. Since the dextromethorphan detection limit of 5 ng/ml achieved in the simultaneous assay for dextromethorphan and its metabolites was not adequate to identify intermediate metabolizers (IMs), 80 of 200 samples selected randomly were also assayed using a modified, more sensitive procedure with a dextromethorphan detection limit of 1 ng/ml. Poor and extensive metabolizers (EMs) could be identified distinctly. A 520-fold interindividual variation in dextromethorphan MRs was observed in this study. In contrast to undetectable dextrorphan and hydroxymorphinan concentrations, clearly determinable dextromethorphan concentrations higher than 10 ng/ml were observed in plasma samples of poor metabolizers (PMs). Considering the antimode of 0.3, five (2.5%, 95% confidence interval of 0.34-4.66) volunteers were identified as PMs. Using the more sensitive method, dextromethorphan was quantified in 4 (one PM) of 80 samples. Excluding the PM, a Shapiro-Wilk test indicated a non-normal distribution of MRs (P < 0.01) in the latter population. From this study it can be concluded that the frequency of PMs in an Iranian population is 2.5% (95% confidence interval of 0.34-4.66). IMs could be identified using dextromethorphan plasma assays with detection limits of at least 1 ng/ml. However, the phenotype-genotype relationships in this respect remain to be established.

Prevention of food-drug interactions with special emphasis on older adults.

Adverse drug interactions may be the fourth leading cause of death in hospitalized patients. In children and older adults undetected food-drug interactions may lead to serious morbidity and mortality and be misdiagnosed as chronic disease progression. Recent recognition of the effects of certain foods on many drugs metabolized by CYP450 families or drugs susceptible to chelation and adsorption have increased awareness for prevention of food-drug interactions. Polypharmacy, self-medications with non-prescription drugs including herbal remedies, dietary/nutritional supplements, fortified foods, and polymorphism in drug metabolism increase the need to consider food-drug interactions. Improved food processing and analysis have led to overall decreased risk in monoamine oxidase inhibitor regimens with counseling. Drugs may create submarginal nutrient deficiencies with serious consequences, such as diuretics contributing to thiamin deficiency and further cardiac failure. Foods may contain compounds that lead to therapeutic failure, such as calcium-fortified foods producing therapeutic failure and promoting resistance in antibiotic therapy. Poor nutritional status can lead to poor health outcomes. Prevention of adverse events from food-herb-drug interactions requires clinical monitoring in high-risk regimens and populations. Nutritional status has an important impact on the quality of life as well as appropriate responses to drug therapy. Both diet-drug histories and counseling are needed. As new foods and drugs emerge and more self-medication is promoted, research in the prevention of food-drug interactions is needed.

Inflammation and Drug Idiosyncrasy—Is There a Connection?

"Drug idiosyncrasy" refers to untoward reactions to drugs that occur in a small fraction of patients and have no obvious relationship to dose or duration of therapy. The liver is a frequent target for toxicity. Much of the conventional thinking about mechanisms of drug idiosyncrasy has centered on hypotheses that the reactions have a metabolic basis involving drug metabolism polymorphisms or that they arise from a specific immune response to the drug or its metabolite(s). For very few drugs does convincing evidence exist for either of these mechanisms, however. The erratic temporal and dose relationships that characterize idiosyncratic drug responses suggest the possibility that some event during the course of therapy renders tissues peculiarly susceptible to toxic effects of the drug. For example, episodes of inflammation are commonplace in people, and results of numerous studies in animals indicate that a modest inflammatory response can enhance tissue sensitivity to a variety of toxic chemicals. These observations have led to the hypothesis that an episode of inflammation during drug therapy could decrease the threshold for drug toxicity and thereby render an individual susceptible to a toxic reaction that would not otherwise occur (i.e., an "idiosyncratic" response). This hypothesis can explain the features of drug idiosyncrasy using fundamental pharmacologic principles, and results of recent animal studies are supportive of this. Knowledge gaps that need to be filled before the hypothesis should be widely accepted are discussed.

Ethnic differences in responses to disease modifying drugs.

The UK has a growing South Asian population. In the South Asian population of Bradford people appear to be less tolerant of disease-modifying anti-rheumatic drugs (DMARDs). One reason for this may be poor communication during patient education, which is generally designed for white North European people. Our objective was to obtain information on DMARDs that were used, the duration of their use and reasons for their discontinuation between ethnic groups. Retrospective data were obtained from the inception of a clinical database in August 1993 to July 2001 using 'DMARD' as the main search item; a total of 5479 DMARD prescriptions were represented in the data. A subset of the data so obtained was cross-checked against the patient records. Inaccuracies in start and stop dates prior to January 1997, together with other reasons (such as incomplete data), resulted in a final data set of 2356 drugs. The drugs had been given to 1391 patients. Overwhelmingly, the two main ethnic groups were North European (1191 patients) and South Asian (193 patients). The final data set was based on the following drugs: azathioprine (179); antimalarials (chloroquine and hydroxychloroquine) (407); corticosteroids (648); D-penicillamine (61); methotrexate (459); sulphasalazine (493); and sodium aurothiomalate (96). Survival analysis showed that age and drug type were important variables influencing the duration of time spent on a drug before discontinuation. For age, drug survival was better for the older age group [log rank test, chi2(3) = 29.1, P < 0.0001]. For drug, survival was best for steroids, followed in decreasing order by sulphasalazine, methotrexate, sodium aurothiomalate, azathioprine, antimalarials and D-penicillamine [chi2(6) = 99.3, P < 0.00001). For all drugs, the main ethnic groups differed, with a 12-month survival rate of drugs in the North European group of 0.742 (95% confidence interval 0.693-0.791) and the South Asian group of 0.665 (95% confidence interval 0.645-0.684) [log rank test, chi2(1) = 18.19, P < 0.00001]. As the two main ethnic groups differed with respect to age and drug type, further survival analysis adjusting for these variables confirmed a significant difference between the two ethnic groups. The main reasons for terminating the DMARD differed between the groups: people of South Asian origin were more likely to discontinue the drug because of rashes, lack of efficacy and worry about the potential side-effects of the drug. People of South Asian ethnic status terminate DMARD therapy sooner than North Europeans. The reasons for this difference are not clear but may concern problems with effective communication, cultural differences in attitudes to chronic illness or genetic polymorphisms in drug metabolism.