Genetic Differences In Drug Metabolism Research Articles

Tools for Community-Based Pharmacist Patient Care Services to Support Optimal Opioid Use

Tools for Community-Based Pharmacist Patient Care Services to Support Optimal Opioid Use

Consistency of Drug–Drug and Gene–Drug Interaction Information in US FDA-Approved Drug Labels

To characterize concordance between clinically relevant drug-drug interactions (DDIs) related to CYP2C19, CYP2D6 and CYP2C9 and their analogous gene-drug interactions (GDIs) in US FDA-approved drug labeling. We selected prototypical CYP2C19, CYP2D6 and CYP2C9 inhibitors and abstracted all respective interacting drugs via a tertiary resource used in the clinical setting. We then selected only CYP2C19, CYP2D6 and CYP2C9 metabolism-related DDIs requiring enhanced clinical monitoring, dose adjustment or use of alternative drugs. Labeling and management strategies on DDIs and GDIs were compared. Among the drug labels with DDI information, 73% of them describe the analogous GDI. Of the 65 drug labels, 43 and 17% had specific management recommendations for DDIs and GDIs, respectively. In general, GDI management recommendations were concordant with DDI management recommendations in terms of specific dose adjustments or use of alternative drugs. The FDA has recognized genetic differences in drug metabolism where clinically relevant DDIs trigger dose adjustment or use of alternative drugs.

Cyclosporine Effects on Pediatric Kidney Recipients

(1), entitled “Cyclosporine trough and 2 hour post dose monitoring and its contributing factors among pediat-ric kidney recipients,” recently published in the Nephro-Urology Monthly. The authors correctly mentioned that there is a negative relationship between cyclosporine A levels (C0 and C2) and serum creatinine. Based on their data, the mean of C0 levels (118 ± 65 ng/mL) was in the therapeutic range, which is an acceptable level of cyclo-sporine after 6 months using the EMIT (Enzyme multi-plied immunoassay technique) assay method (2). Then lower serum creatinine levels that better reflects graft function are predictable. Although in this study, the mean of C2 levels (471 ± 148 ng/mL) was lower than thera-peutic levels (600-800 ng/mL), patients had good graft function. This result can be explained by previous simi-lar studies in Iran in which most patients at therapeutic C2 levels presented with cyclosporine nephrotoxicity or the recipients did not reach target levels, so they didn’t recommend routine checking of C2 levels (2, 3). This may be due to genetic differences in drug metabolism in dif-ferent races which can lead to different peak levels or dif-ferent peak times (for example 3 or 4 hours after taking) in Iranian patients.Another factor that may impact on graft function con-sists of the donor’s demographic data such as type (ca-daveric

Abstract P138: Quality Improvment Strategy for Better Control of Warfarin Anticoagulaton in Outpatients

Introduction: Warfarin is currently the only effective oral anticoagulant for thromboembolic prophylaxis in patients at high risk for stroke or other thromboembolic complications. Maintaining a therapeutic level of anticoagulation as measured by the International Normalized Ratio (INR) can be challenging, due to genetic differences in drug metabolism, multiple drug interactions, and variations in dietary vitamin K intake. We designed a program to improve our ability to keep our patients' INR within the therapeutic range. Methods: We established a baseline degree of INR control in the fall of 2007, measuring the INR for 50 sequential patients who required warfarin therapy for at least one month for each of our 5 physicians; therapeutic range was 2-3 for most indications, or 2.5-3.5 for mechanical valves. We then instituted an INR improvement program, making certain our office gave directions for subsequent warfarin dosing and the next INR testing directly to the patient only; reviewing all drugs and potential interactions at each contact; reviewing potential dietary and alcohol consumption issues at each contact; and utilizing a standard dosing protocol for any dose changes. We reassessed the degree of INR control 6 months later and 18 months later in a similar cohort, measuring 50 sequential patients for each of our 5 physicians. Results: At our most recent survey, the average age of our patients was 73.7 and 43% (108 of 250) were female. The indication for anticoagulation was atrial fibrillation in 81.6% (204 of 250), mechanical heart valve in 11.2% (28 of 250), and other indications in 7.2% (18 of 250). The percentage of patients within their therapeutic range was 62.4% (156 of 250) at the baseline survey, 66.0% (165 of 250) at the second survey, and 65.6% (164 of 250) at the most recent survey, p=0.42 comparing first to second, p=0.45 comparing first to third, and p=0.92 comparing second to third, none significantly different. Conclusion: Achieving and maintaining a therapeutic INR with warfarin dosing even with an aggressive quality improvement program is a continuing therapeutic challenge. More effective management strategies or alternative anticoagulants which may be simpler to manage remain a high priority.

Pharmacogenomics Can Predict Patient Responses

Pharmacogenomics Can Predict Patient Responses

Abstract ED05-02: Common drugs associated with reduced cancer risk

Abstract The list of commonly used medications thought possibly to be associated with a reduction in risk of cancer is constantly growing. Among these drugs are aspirin, NSAIDs, Cox-2 inhibitors, statins, bisphosphonates, HRT, levothyroxine, colchicin, allopurinol, and the antiglycemic drug metformin. Most of these medications show an association with risk reduction across different cancer sites; some are more specific to one type of cancer while others may reduce risk in one site and increase risk in another. Biological pathways of anticancer activity have been suggested for most of the abovementioned medications and relevant cancer biomarkers can support, but not prove, the suggested associations. Most data on commonly used medications come from observational studies since most of these drugs have not been studied in randomized controlled trials (RCTs) with cancer as a predefined endpoint. Data from observational studies are prone to a variety of biases making their use problematic. Data from retrospective studies on medications used for a single clinical indication are also problematic as it is hard to separate the potential preventive effect of the drug from the possible association between the disease (for which the drug was given) and cancer. Most of these commonly used medications are off-patent and therefore there is no incentive for the pharmacological industry to test them in RCTs for anticancer effects. RCTs might also not be feasible for the study of widely used drugs, both because of the high risk of contamination of the control arm as well as the selectivity and nonrepresentativeness of the participants who are not already taking these medications. Well designed association studies combined with supporting biomarkers data might be the only source of evidence for decision making on this subject. Alternatively, whether such common drugs actually have cancer prevention effects might only be alluded to through a natural experiment where reduction in cancer incidence will occur concurrently with an increase in the use of these drugs. The literature is full of conflicting reports on the association of medications with cancer risk. There are many factors that can contribute to this — differences in types of studies, in class of medication within a pharmacological group (for example simvastatin vs. atorvastatin), in dosage, length of use, mode of delivery (oral, IV, patch), or in type of population studied (genetic differences in drug metabolism). We the lack of RCT results, all of these elements need to be taken into account when trying to conduct a meta-analysis of the currently available data and to reach a conclusion regarding to the true cancer prevention qualities of the relevant medications. While the current data are very promising, all of these pitfalls add to the difficulty in understanding the true association between commonly used medications and cancer risk and might delay their incorporation into routine clinical practice. Citation Information: Cancer Prev Res 2010;3(12 Suppl):ED05-02.

Predictors of response to anti-TNF- therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register

Anti-tumour necrosis factor-alpha (TNF-alpha) therapies represent an important advancement in therapy for rheumatoid arthritis (RA). However, there remains a proportion of patients who do not improve despite therapy. These drugs are expensive and have the potential of serious toxicity. Therefore, it would be ideal to predict the patients who will respond, so that the use of these drugs can be targetted. To identify the clinical factors present at the start of anti-TNF-alpha therapy that are associated with response at 6 months in patients with RA. The British Society for Rheumatology (BSR) Biologics Register collects detailed data on all patients with a rheumatic disease receiving biologic therapy in the UK. We studied all patients with RA who had started etanercept (ETA) or infliximab (INF) and had achieved a minimum 6 months follow-up by 1 October, 2004. The disease status at the baseline and at 6 months was assessed using the Disease Activity Score (DAS28). The response was classified according to the European League against Rheumatism (EULAR) improvement criteria. The effect of baseline characteristics on response was studied using multivariate ordinal logistic regression. 2879 patients were included in this analysis (1267 ETA, 1612 INF). At the start of therapy, the mean age was 55 yrs, disease duration 14 yrs, baseline DAS28 6.7 and health assessment questionnaire (HAQ) 2.1. In all, 28% of ETA and 86% of INF patients were receiving methotrexate. After 6 months, 18% had a good EULAR response, of whom 9% were considered to be in remission and 50% had a moderate response. There was no overall difference in response rate between the two anti-TNF-alpha therapies. A higher baseline HAQ score correlated with a lower response rate while a better response was associated with the current use of NSAIDs and the use of methotrexate (MTX), although the latter only reached statistical significance with ETA [OR 1.82 (95% CI 1.38-2.40)]. There was a lower response rate among current smokers, particularly in patients receiving INF [OR 0.77 (95% CI 0.60-0.99)]. Age, disease duration, rheumatoid factor and the previous number of disease-modifying antirheumatic drugs (DMARDs) did not predict response to either drug. However, females were less likely to achieve remission. These data support an improved outcome among patients receiving MTX in combination with anti-TNF-alpha therapies. However, the most disabled patients were less likely to respond, despite concurrent MTX. The benefits of NSAIDs may reflect the relative absence of comorbidities in patients who can tolerate these drugs or the continuing presence of reversible inflammatory symptoms. The association of smoking and poor outcome with INF is a novel finding and may reflect alterations in pharmacokinetics. The inability of other baseline disease characteristics to predict the outcome suggests that other factors, including potential genetic differences in drug metabolism, may be influencing the response to anti-TNF-alpha therapies.

P450 Oxidoreductase Deficiency: A New Disorder of Steroidogenesis Affecting All Microsomal P450 Enzymes

Combined partial deficiency of 17α‐hydroxylase and 21‐hydroxylase activities was first described in 1985; however the genes for P450c17 and P450c21 in these patients lack mutations. In 1986 we postulated that this disorder might be due to mutations in P450 oxidoreductase (POR), the flavoprotein that donates electron to these and all other microsomal P450 enzymes, but this hypothesis was not tested until the POR gene sequence became available through the genome database. We found five POR missense mutations in our first four patients. In vitro assays of the activities of these mutations showed that the standard assay of POR activity, reduction of cytochrome c, correlated poorly with the patients' phenotypes, but that assays of POR‐supported 17α‐hydroxylase and 17,20 lyase activities correlated well. POR deficiency is a new disorder of adrenal and gonadal steroidogenesis that affects all microsomal cytochrome P450 enzymes, hence may have important implications for genetic differences in drug metabolism.

Use of body surface area to calculate chemotherapeutic drug dose in dogs: II. Limitations imposed by pharmacokinetic factors.

Anticancer drug dosages that specify the maximum dose and minimum dosing interval that are tolerated in a population of dogs are commonly recommended. Because the differences between the effective and toxic doses of most cancer chemotherapeutics is slight, it is important to achieve therapeutic concentrations in tumor tissues at the same time that concentrations in nontarget tissues are minimized. In order to determine the dosage regimen that will most likely accomplish these goals, similar drug concentrations must be achieved in all patients dosed according to a specific regimen. Dosing based on body surface area (BSA) is generally used in an effort to normalize drug concentrations. This is because it is well recognized that measures of many physiologic parameters that are responsible for drug disposition, including renal function and energy expenditure, can be normalized by use of BSA. However, there is substantial evidence that drug disposition is not always proportional to BSA. Differences in distribution, metabolism, and excretion pathways may preclude dose extrapolation among species or among individuals within a species based on BSA. Moreover, genetic differences in drug metabolism are well recognized in humans and in laboratory animals, and it is likely that similar differences exist among breeds of dogs. A review of the pharmacokinetic disposition of several cancer chemotherapeutics suggests that studies are needed to determine the most effective method to achieve equivalent anticancer drug concentrations in diverse veterinary patients.

Thalidomide-induced neuropathy and genetic differences in drug metabolism.

A pharmacogenetic predisposition to thalidomide-induced neuropathy has been investigated. Differences of drug metabolism were examined in 16 patients with severe orogenital ulceration, who were treated with thalidomide (< or = 200 mg/day) for 0.3-5.0 years. Eight had evidence of early peripheral neuropathy according to nerve conduction studies. Rates of C-hydroxylation, N-acetylation, and conjugation reactions with sulphate, glucuronide and glycine, were tested with the probe compounds debrisoquine, sulphadimidine, paracetamol and aspirin, respectively. Urinary drug metabolites were analysed by high pressure liquid chromatography. Results were compared with 16 healthy age- and sex-matched volunteers. Of the patients 6.25% and 13.3% of the controls had a poor Debrisoquine Hydroxylator Ratio (DMR); none of the patients with neuropathy had a poor DMR as compared to 12.5% without neuropathy. Of the patients 40.0% and 35.7% of the controls were slow acetylators; 28.6% with neuropathy were slow acetylators as opposed to 50% without neuropathy. Similarly, there were no significant differences in rates of conjugation between groups. All unaffected patients were active smokers, whereas only two of those with neuropathy smoked. Cumulative dose or duration of therapy were unrelated to risk of neuropathy. In conclusion, changes of nerve conductivity are a frequent and unpredictable adverse effect of thalidomide (< or = 200 mg/day), although smoking may have a protective action against their development. Nerve conduction studies are required before and during treatment, irrespective of the prescribed dose.

Identification of genetic differences in drug metabolism: Prediction of individual risk of toxicity or cancer

These two reports describe recombinant DNA tests that can identify individuals having a defect in the cytochrome P450IID6 (CYP2D6)-mediated oxidative metabolism of debrisoquine and more than two dozen other drugs that are commonly prescribed. The poor metabolizer (PM), representing 5% to 10% of the northern European white population is homozygous for an autosomal recessive trait. Compared with the extensive metabolizer (EM) phenotype, the PM individual is more prone to toxicity caused by some of these drugs. Curiously, the PM phenotype appears to be associated with a lower risk of lung and bladder cancer. Gough and coworkers propose that the primary gene defect associated with the CYP2D6 polymorphism appears to be a G to A transition mutation affecting the splice junction of intron 3/exon 4 of the CYP2D6 gene. They offer a polymerase chain reaction (PCR) amplification method for diagnosing three variant alleles and claim to have predicted the phenotype of all normal and 34 of 42 (81%) PM individuals. Based on the known frequencies of those variant alleles detectable by this method, however, the assay would be expected to predict less than 60% of PM patients. Heim and Meyer, on the other hand, have combined allelespecific PCR with restriction fragment length polymorphism (RFLP) patterns to identify more than 95% of all mutant alleles, suggesting that their assay would accurately predict more than 90% of all PM individuals. Using this latter assay or a similar test with further improvements, especially in combination with family studies, it should soon be possible for the physician to determine the CYP2D6 phenotype of the patient, thereby avoiding toxic drug overdoses.

Identification of genetic differences in drug metabolism: Prediction of individual risk of toxicity or cancer Gough AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, Eichelbaum M, Wolf CR. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 1990;347:773–776. Heim M, Meyer UA. Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 1990;336:529–532

Identification of genetic differences in drug metabolism: Prediction of individual risk of toxicity or cancer Gough AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, Eichelbaum M, Wolf CR. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 1990;347:773–776. Heim M, Meyer UA. Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 1990;336:529–532

Tolerability and Kinetics of Intravenous Medifoxamine in Healthy Volunteers

Medifoxamine is a new antidepressant drug which is in clinical use in France and is undergoing clinical investigation elsewhere. We have carried out a study of its tolerance by the intravenous route and have investigated its kinetic parameters by this route. Twelve healthy volunteers received single ascending intravenous doses of medifoxamine 5 to 10 mg. The subjects were observed for changes in haemodynamic and other vital signs. Serum samples were analyzed using a specific HPLC method. Medifoxamine was well tolerated by all volunteers. Its kinetics were described by a two-compartment open model with an elimination half-line 1.2 h, systemic clearance 1299 l/min, volume of distribution 1321 l and urinary excretion of parent drug less than 1% of the dose. One subject had high serum concentrations and low clearance when compared with the other subjects. This may have been due to genetic differences in drug metabolism, as this subject was found to be a poor metabolizer of debrisoquine.

Genetics of Responses to Drugs of Abuse

Genetic differences in drug metabolism, in the number of drug receptors in the brain, and in drug-seeking behavior may contribute to the variability of individual responses to drugs of abuse. Genetic models include inbred strains, mutants, sublines, and selectively bred mice and rats. They have been used to examine acute and chronic effects of narcotics, stimulants, and alcohol as well as drug-seeking behavior, withdrawal syndromes, and the stress-induced release of endogenous opioids. These genetic models should prove helpful in defining individual differences in susceptibility to addiction.

Pharmacogenetics of methylation: Relationship to drug metabolism

Pharmacogenetics is the study of inherited variation in drug response. Genetic differences in drug metabolism are the most common causes for inherited variations in drug response or adverse reactions to medications. Methyl conjugation is an important pathway in the biotransformation of many drugs. Experiments performed during the past decade showed that individual variations in the activities of enzymes that catalyze S-methylation, O-methylation and N-methylation are under genetic control in human tissue. These inherited variations are responsible for individual differences in metabolism, effect, and toxicity of drugs that undergo methyl conjugation. The approach used to study the pharmacogenetics of methylation may also be applicable to the study of inherited variations in other pathways of drug metabolism.

The Clinical Significance of Retarded Hepatic Drug Metabolism

The Clinical Significance of Retarded Hepatic Drug Metabolism

Genetic Differences in Drug Metabolism Associated with Ocular Toxicity

The tissue localization and subcellular distribution of drug-metabolizing enzymes in the eye are described. With the use of inbred strains of mice, the [Ah] complex is shown to be an important experimental system for probing genetic differences in drug metabolism and related drug toxicities. Although the genetic system described in detail here involves mice, there is ample evidence that the same system operates in man. Genetic differences in acetaminophen- and naphthalene-induced cataract formation and and other ocular degeneration are shown to be related to the [Ah] complex. Because this toxicity appears similar to senile cataracts, we propose that certain types of drug-induced cataracts might exist among clinical populations of senile cataracts but that any cause-and-effect relationship would be very difficult to determine because of underlying interindividual differences in genetic predisposition. It is therefore suggested that genetic differences in drug metabolism be an important consideration in the clinical assessment of ocular toxicity caused by drugs and other environmental pollutants.

Genetic differences in drug metabolism associated with ocular toxicity.

The tissue localization and subcellular distribution of drug-metabolizing enzymes in the eye are described. With the use of inbred strains of mice, the [Ah] complex is shown to be an important experimental system for probing genetic differences in drug metabolism and related drug toxicities. Although the genetic system described in detail here involves mice, there is ample evidence that the same system operates in man. Genetic differences in acetaminophen- and naphthalene-induced cataract formation and and other ocular degeneration are shown to be related to the [Ah] complex. Because this toxicity appears similar to senile cataracts, we propose that certain types of drug-induced cataracts might exist among clinical populations of senile cataracts but that any cause-and-effect relationship would be very difficult to determine because of underlying interindividual differences in genetic predisposition. It is therefore suggested that genetic differences in drug metabolism be an important consideration in the clinical assessment of ocular toxicity caused by drugs and other environmental pollutants.

Clinical pharmacology. Possible clinical importance of genetic differences in drug metabolism.

Clinical pharmacology. Possible clinical importance of genetic differences in drug metabolism.