David W. J. Clark

Genetically determined variability in acetylation and oxidation: therapeutic implications

SummaryThe clinical significance of two separate genetic polymorphisms which alter drug metabolism, acetylation and oxidation is discussed, and methods of phenotyping for both acetylator and polymorphic oxidation status are reviewed. Particular reference is made to the dapsone method, which provides a simple means of distinguishing fast and slow — and possibly intermediate — acetylators, and to the sparteine method which allows a clear separation of oxidation phenotypes.Although acetylation polymorphism has been known for some time, definite indications for phenotyping are few. It is doubtful whether acetylator phenotype makes a significant difference to the outcome in most isoniazid treatment regimens, and peripheral neuropathy from isoniazid in slow acetylators is easily overcome by pyridoxine administration. However, in comparison with rapid acetylators, slow acetylators receiving isoniazid have an increased susceptibility to Phenytoin toxicity, and perhaps also to carbamazepine toxicity. It is also possible that rapid acetylators receiving isoniazid attain higher serum fluoride concentrations from enflurane and similar anaesthetics than do similarly treated slow acetylators. Thus, when drug interactions of these types are suspected, phenotyping for acetylator status may be advisable.If routine monitoring of serum procainamide and N-acetylprocainamide concentrations is practised, phenotyping of subjects prior to therapy with these agents should not be necessary. Although acetylator phenotype influences serum concentrations of hydralazine, when this drug is given in combination with other drugs acetylator phenotype has not been shown to influence the therapeutic response. Slow acetylator phenotype along with female gender and the presence of HLA-DR antigens appear to be risk factors in the development of hydralazine-induced systemic lupus erythematosus (SLE). Determination of acetylator phenotype may therefore help determine susceptibility to this adverse reaction. In the case of sulphasalazine, adult slow acetylators require a lower daily dose of the drug than fast acetylators in order to maintain ulcerative colitis in remission without significant side effects. It is therefore advisable to determine acetylator phenotype prior to sulphasalazine therapy.Work on the association of acetylation polymorphism with various disease states is also reviewed. It is possible that a higher incidence of bladder cancer is associated with slow acetylation phenotype — especially in individuals exposed to high levels of arylamines. The question as to whether idiopathic SLE is more common in slow acetylators remains unresolved. There appears to be no difference between fast and slow acetylators in susceptibility to generalised rheumatoid arthritis, but slow acetylators may be more common amongst rheumatoid arthritis patients with Sjögren’s syndrome than amongst rheumatoid patients without this syndrome. An excess of slow acetylators has been noted in patients with Gilbert’s syndrome, but the clinical significance of this is uncertain.Polymorphic oxidation, characterised by the impaired ability of between 5 and 10% of the population to oxidise debrisoquine or sparteine, has been known for a much shorter time than has polymorphic acetylation, and work on the clinical significance of this polymorphism is far from complete. A number of β-adrenoceptor blocking drugs, e.g. metoprolol, have been shown to share the same oxidation pathway as debrisoquine and sparteine, but so far this has not been demonstrated to be of clinical importance. However, the incidence of peripheral neuropathy after perhexiline has been shown to be significantly increased in poor oxidisers. Determination of oxidation status prior to use of this drug could help to determine dosage and to control its neurotoxicity.The kinetics of certain tricyclic antidepressants, including nortriptyline and desipramine, are related to oxidation status but the full clinical significance of this is not known. The oxidation of Phenytoin is only partly affected by the form of cytochrome P-450 involved in sparteine and debrisoquine oxidation. As measurement of Phenytoin blood concentrations provides a guide to dosage, phenotyping with debrisoquine or sparteine is not justified.Encainide requires oxidation in the body for it to have significant antiarrhythmic activity, and reduced activity in poor oxidisers of debrisoquine has been noted. Prior phenotyping for oxidation status may therefore be advisable before treatment with this drug. Several other drugs, not now widely used clinically, have also been shown to share the debrisoquine/sparteine oxidation pathway (e.g. guanoxan, phenacetin, metiamide, phenformin, and methoxyamphetamine) and this has implications with regard to the toxicity of these drugs.Genetic polymorphisms in drug metabolism should be allowed for in the development and monitoring of new drugs. Other oxidation pathways not associated with debrisoquine or sparteine (such as that of tolbutamide, mephenytoin and S-carboxymethyl-L-cysteine) may also involve genetic polymorphisms. Clinicians and others in the health-care team, when confronted with an adverse drug reaction, should bear in mind the possible influence of genetic polymorphism.

Pharmacoeconomic Analyses of Azathioprine, Methotrexate and Prospective Pharmacogenetic Testing for the Management of Inflammatory Bowel Disease

AbstractObjectives: To compare the cost effectiveness of azathioprine (AZA), methotrexate (MTX) and no immunosuppression for maintaining remission of moderate to severe inflammatory bowel disease (IBD) in New Zealand Caucasians, and to determine whether prospective testing for poor metabolisers of AZA by genotype or phenotype is cost effective. Methods: Pharmacoeconomic models were developed to compare treatment costs and effects (QALYs) in theoretical populations of 1000 IBD patients over a 1-year period. Efficacy and tolerability profiles for AZA and MTX were taken from the literature. The costs (year 2004 values) of the drugs and treatment of adverse effects were estimated from New Zealand drug and service costs. Representations of the patients’ health-related quality of life (HR-QOL) were obtained from clinicians via the EQ-5D health state classification system and valued using the New Zealand EQ-5D social tariff. The effects of genotyping or phenotyping a population for thiopurine methyltransferase (TPMT) status were compared using the prevalence of TPMT deficiency in Caucasians, the relative risks of neutropenia and the associated costs. Results: Net cost savings (vs no immunosuppressant treatment) of approximately

Do some inhibitors of COX-2 increase the risk of thromboembolic events? Linking pharmacology with pharmacoepidemiology

NZ2.5 million and

Clinical Implications of Pharmacogenetic Variation on the Effects of Statins

NZ1 million were realised for AZA and MTX, respectively, for the theoretical 1000 patients, and AZA generated 877 QALYs compared with 633 for MTX. Phenotype and genotype testing generated net cost savings (vs no testing) of

Effects of Immunosympathectomy on Development of High Blood Pressure in Genetically Hypertensive Rats

NZ120 000 and

Monitoring the safety of over the counter drugs. We need a better way than spontaneous reports.

NZ11 000, respectively. Savings related to phenotype tests were greater because of the lower assay costs of phenotype testing and a greater likelihood of pre-empting neutropenia. Conclusion: Our model suggests that both MTX and AZA may generate significant net cost savings and benefits for patients with IBD in New Zealand, with AZA likely to be more cost effective than MTX. Prospective testing for poor metabolisers of AZA may also be cost effective, with phenotype testing likely to be more cost effective than genotype testing.

Profiles of hepatic and dysrhythmic cardiovascular events following use of fluoroquinolone antibacterials: experience from large cohorts from the Drug Safety Research Unit Prescription-Event Monitoring database.

Inhibitors of the cyclo-oxygenase (COX)-2 isoenzyme were developed with the expectation that their use would be accompanied by a reduction in adverse reactions thought to be mediated through COX-1 compared with conventional nonselective NSAIDs. However, the results of some clinical studies and other evidence have led to the hypothesis that use of COX-2 inhibitors may contribute to an increased risk of adverse thromboembolic (TE) events. In this review, we have evaluated the evidence from small-scale in vitro and in vivo pharmacological studies, clinical trials and large-scale pharmacoepidemiological studies and commented on the relationship between the pharmacological characteristics related to thromboembolic events and the clinical effects in large-scale clinical trials and pharmacoepidemiological studies.Overall, the pharmacological evidence suggests that a prothrombotic effect of COX-2 selective inhibitors is plausible. To date, despite the results from the Vioxx Gastrointestinal Outcome Research (VIGOR) study from which the clinical concern regarding cardiovascular TE risk arose, the published data from other randomised controlled trials (RCTs), retrospective observational studies and spontaneous reporting schemes provide a conflicting body of evidence on the TE risk with COX-2 inhibitors.Concerns that COX-2 inhibitors may be associated with prothrombotic effects remain and these need to be addressed in large scale, RCTs designed specifically to investigate the possibility of an excess of adverse cardiovascular outcomes in users of some or all selective COX-2 inhibitors, both with and without concomitant low-dose aspirin (acetylsalicylic acid). Consideration must also be given to other pathophysiological mechanisms for potential cardiovascular risk linked with inhibition of COX-2.In view of the evidence reviewed, it is recommended that selective COX-2 inhibitors should be prescribed with caution, only in patients with conditions for which these drugs have proven efficacy and with careful monitoring of outcomes and adverse events. This is particularly important in the elderly, in patients with cardiovascular/renal disease and in patients with other risk factors that might predispose them to adverse events.

Linking Pharmacovigilance with Pharmacogenetics

The last decade has seen an increase in the trend of HMG-CoA reductase inhibitor (statin) usage in the Western world, which does not come as a surprise noting that the latest American Heart Association heart and stroke statistics indicate an alarming prevalence of 80 million Americans (one in three) with one or more forms of diagnosed cardiovascular disease (CVD). Meta-analysis of several large-scale, randomized clinical trials has demonstrated statins to be efficacious in significantly reducing CVD-associated mortality in both primary and secondary prevention. Despite their proven efficacy, statins have also gained attention with respect to adverse drug reactions (ADRs) of muscle myopathy, derangements in hepatic function and even ADRs classified as psychiatric in nature. The depletion of cholesterol within the myocyte cell wall and/or the depletion of key intermediates within the cholesterol synthesis pathway are hypothesized as possible mechanisms of statin-associated ADRs. However, pharmacogenetic variability may also be a risk factor for ADRs and can include, for example, enzymes, transporters, cell membrane receptors, intracellular receptors or components of ion channels that contribute to the pharmacokinetics or pharmacodynamics of response to a particular drug. The cytochrome P450 (CYP) enzymatic pathways that comprise the polymorphic genes, CYP2D6, CYP3A4 and CYP3A5, and also a hepatic transporter, solute carrier organic anion transporter (SLCO1B1), which is a single nucleotide polymorphism discovered to be associated with statin-induced myopathy through a genome-wide association study, are discussed with respect to their effect on altering the pharmacokinetic profile of statin metabolism. Variants of the Apolipoprotein E (APO-E) gene, polymorphisms in the cholesteryl ester transfer protein (CETP) gene, the HMG-CoA reductase gene and other proteins are discussed with respect to altering the pharmacodynamic profile of statins. Pharmacogenetics and its application in medicine to individualize drug therapy has been previously shown to be clinically and economically beneficial through quality-adjusted life-year assessment. Therefore, polymorphisms affecting the pharmacokinetic and pharmacodynamic profiles of statins, which are widely used in therapy, with their potential application in the personalized prescribing of statin therapy, need further research. In this review, we update the recent literature with respect to genetic polymorphisms that may influence the pharmacokinetics and pharmacodynamics of statin therapy, and consider the relevance of these findings to the efficacy of treatment, prevention of ADRs and what this may mean for patient tolerance and compliance.

The Role of the New Zealand Intensive Medicines Monitoring Programme in Identification of Previously Unrecognised Signals of Adverse Drug Reactions

Newborn male rats from the New Zealand colony with genetic hypertension (hypertensive rats) and from a normotensive colony (controls) were immunosympathectomized by injections of antiserum to nerve growth factor. Blood pressure of immunosympathectomized hypertensive rats aged 63 days (128±2 mm Hg) was significantly less (P<.001) than that of untreated hypertensive rats (176±3 mm Hg) of the same age. Pressure of immunosympathectomized controls aged 63 days (107±2 mm Hg) was significantly less (P<.001) than that of untreated controls (126±1 mm Hg) at the same age. Pressure thereafter remained near these levels. In immunosympathectomized rats, ganglion blockade with supramaximal doses of hexamethonium still induced a lar51ge fall in pressure which was significantly lower than in untreated rats. The combination of immunosympathectomy and hexamethonium brought the pressure of hypertensive rats and controls down to the same level (68 mm Hg). The pressor response to intravenous norepinephrine was greater in immunosympathectomized than in untreated rats. Resistance to flow in perfused mesenteric arteries from immunosympathectomized hypertensive rats was significantly less (P<.05) than in arteries from untreated hypertensive rats. Hearts of immunosympathectomized hypertensive rats were significantly lighter (P<.01) than those of untreated hypertensive rats. Heart rates of hypertensive or control rats were not altered by immunosympathectomy.

Neuropsychiatric reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). The New Zealand experience.

Last year the Food and Drug Administration in the United States recommended that phenylpropanolamine be removed from non-prescription and prescription medicines and that pharmaceutical companies voluntarily discontinue products containing phenylpropanolamine. This was in response to a case-control study by the Yale haemorrhagic stroke project investigators designed to determine the risk of haemorrhagic stroke in people exposed to phenylpropanolamine.1 Though this action was not followed in the United Kingdom, because the market conditions for phenylpropanolamine are different, the findings of the haemorrhagic stroke project highlight the need for continued monitoring of the safety of non-prescription medicines. In the United States formulations of phenylpropanolamine contain up to 150 mg of a racemic mixture of two enantiomers of (±)-norephedrine,2 and withdrawal of appetite suppressants and cough and cold preparations containing phenylpropanolamine may well have been an appropriate response to the haemorrhagic stroke project data. In Europe the licensed maximum daily dose in non-prescription cough and cold remedies is lower (100 mg), and appetite suppressants containing phenylpropanolamine are not available in the United Kingdom. …