Cytochrome System Research Articles

Genetic Polymorphisms of CYP2C8 in the Czech Republic

CYP2C8 represents 7% of the hepatic cytochrome system and metabolizes around 5% of drugs in phase I processes. It also plays a significant role in metabolism of endogenous compounds. More than 20 single-nucleotide polymorphisms (SNPs) have been noted, mainly in exons 3, 5, and 8. The most studied SNPs may lead to decreased enzyme activity and may have impact on drug metabolism. Variant alleles are called CYP2C8*2 (I269F), CYP2C8*3 (R139K, K399R), and CYP2C8*4(I264M). Our aim was to investigate the frequency of major functional SNPs among the Czech population. DNA was isolated from whole blood of 161 healthy, young, and unrelated subjects (94 men and 67 women, aged from 23 to 28 years). The genotypes of polymorphic positions CYP2C8*2, CYP2C8*3 (G416A, A1196G), and CYP2C8*4 were determined by polymerase chain reaction-restriction fragment length polymorphism. Observed allele frequencies were 10.9%, 5.9%, and 0.3% for the alleles CYP2C8*3, CYP2C8*4, and CYP2C8*2, respectively. Both CYP2C8*3 (G416A, A1196G) alleles have been found in complete linkage disequilibrium. The allele distribution complies well with Hardy-Weinberg equilibrium. Allele frequencies of functionally important CYP2C8 variants in the Czech population are similar to that of other Caucasian populations.

Pharmacogenetics of Obsessive–Compulsive Disorders

Genetic factors have been shown to influence occurrence and severity of several psychiatric disorders and also to modulate outcome to drug treatment. Obsessive-compulsive disorder (OCD) is a severe psychiatric condition with clear genetic roots; there is also some evidence to suggest that genetic factors may impact on response to drug treatment. Typically between 40 and 60% of patients are deemed nonresponders to antidepressant medication and clinical factors have only been modestly correlated with treatment response. Thus, identification of biological factors which may relate to treatment response could be extremely valuable in improving clinical outcome. In this article, we briefly review previous work regarding clinical and demographical factors associated with drug response in OCD, then focus on recent findings regarding candidate genes which may influence drug response, including those in the serotonin system, brain-derived neurotrophic factor and the glutamate transporter gene. The cytochrome system may also be highly relevant to drug response. Thus far, relatively few studies regarding the pharmacogenetics of OCD have been published, and therefore further investigation with functional analyses and consideration of environmental factors are warranted to facilitate clinical use of pharmacogenetic findings in the future.

P-10 Accuracy in public reporting of healthcare utilization and adverse events in a community hospital

mented appropriate administration of the medication. Methods: Upon literature review, a significant, but highly variable portion of pre-systemic metabolism by the P450 and other metabolizing enzymes occurs in the proximal small bowel. Bypass of this important first pass clearance mechanism provided increased delivery and bioavailability of active drug to the distal small bowel, leading to toxicity with absorption. Results: Many factors contribute to the wide variability of human pre-systemic metabolism of pharmaceuticals and other compounds, and RGB may significantly change drug pharmacokinetics. While many patients are able to quickly come off some medications after surgery, the immediate post-bypass weeks provide a high risk period for abnormally high drug bioavailability, with sometimes seemingly paradoxical increase in serum drug levels. Conclusion: Further studies on pharmaceutical and herbal medications are necessary to understand kinetics and dynamics in gastric bypass patients. Caution should be exercised when restarting medications postoperatively, particularly with compounds known to be metabolized by the P450 cytochrome system. Frequent monitoring, rapid weaning as able and education of all members of the health care team are indicated.

The effect of cetyltrimethylammonium bromide on the cytochrome system of Escherichia coli.

The effect of cetyltrimethylammonium bromide on the cytochrome system of Escherichia coli.

Pondering the Significance of PON1

Another strong pharmacogenetic variant for clopidogrel response emerges.

Clinical evidence of interaction between clopidogrel and proton pump inhibitors

Clopidogrel is approved for reduction of atherothrombotic events in patients with cardiovascular (CV) and cerebrovascular disease. Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after acute coronary syndrome or percutaneous coronary intervention, compared with aspirin alone. Due to concern about gastrointestinal bleeding in patients who are receiving clopidogrel and aspirin therapy, current guidelines recommend combined use of a proton pump inhibitor (PPI) to decrease the risk of bleeding. Data from previous pharmacological studies have shown that PPIs, which are extensively metabolized by the cytochrome system, may decrease the ADP-induced platelet aggregation of clopidogrel. Results from retrospective cohort studies have shown a higher incidence of major CV events in patients receiving both clopidogrel and PPIs than in those without PPIs. However, other retrospective analyses of randomized clinical trials have not shown that the concomitant PPI administration is associated with increased CV events among clopidogrel users. These controversial results suggest that large specific studies are needed. This article reviews the metabolism of clopidogrel and PPIs, existing clinical data regarding the interaction between clopidogrel and PPIs, and tries to provide recommendations for health care professionals.

Enhanced Clopidogrel Responsiveness in Smokers

Observational studies have reported enhanced response to clopidogrel in smokers (the smokers' paradox). We examined whether genetic variations in the cytochrome and drug transporter system are associated with the effect of smoking on clopidogrel response. Clopidogrel on-treatment platelet reactivity (OPR) was measured in 1431 consecutive patients who underwent coronary angiography. Gene samples were available and genotyping was successful in 1123 patients. Nine candidate single-nucleotide polymorphisms in 5 cytochrome genes and 1 drug transporter gene were assessed. The mean OPR of the entire population was 241.9 ± 79.3 (P2Y(12) reaction units). Two hundred forty-nine (17%) smokers had lower OPR compared with 1182 (83%) nonsmokers (227.6 ± 76.0 versus 244.9 ± 79.7, P=0.001). Among the 9 single-nucleotide polymorphisms, only CYP1A2 showed a genotype-dependent change in the effect of smoking on OPR. After adjustment for possible confounding factors, cigarette smoking was associated with a lower OPR by -19 P2Y(12) reaction units (P=0.009) and lower risk for high OPR (odds ratio [OR], 0.48; 95% CI, 0.31 to 0.74) in the AA and CA genotypes but not in the CC genotype. Enhanced clopidogrel response in smokers, known as the smokers' paradox, is not universal but was observed only in cytochrome P450 CYP1A2 (-163C>A) A-allele carriers, suggesting a genotype-dependent effect of smoking on clopidogrel responsiveness.

Leflunomide: A Drug with a Potential Beyond Rheumatology

Leflunomide, an inhibitor of the dihydroorotase dehydrogenase and thereby pyrimidine synthesis, was introduced and licensed for the treatment of rheumatoid arthritis in 1998. In the following years, its antiviral properties were discovered and the drug was used in solid organ transplantation for polyomavirus type BK or cytomegalovirus infection. Owing to its long half-life and weak interaction with the cytochrome system, special considerations apply in the use of this drug. This article summarizes the clinical experience with leflunomide in rheumatology and in the evolving field of transplantation.

Tolerability of antiretroviral therapy (HAART) in elderly age

Background The median age of people living with HIV/AIDS is increasing: while efficacy of HAART has reduced mortality and prolonged the life of patients, low perception of risk and new late diagnosis are related to infection in an elderly age. Most new late diagnosis are performed in older hardly immuno-compromised subjects; the development of opportunistic diseases complicates management of therapeutic strategies (drugs interactions, cumulative toxicities, hypersensitivity reaction), mainly in presence of comorbities. Most randomized clinical trials with new drugs tend to avoid the enrolment of >50 years patients with proper comorbities of old age. So the few data we can analyze come from observational cohorts. While it is well defined that older people are more adherent to treatment and achieved an adequate control of HIV-RNA viremia more frequently than younger although an incomplete immuno-reconstitution, the development of drug toxicity with higher frequency is controversial. Elderly people are more frequent to show reduced hepatic and kidney function, frequently have comorbities requesting new therapies with a higher pill burden and higher risk of drug interactions. Most antiretroviral drugs are metabolized by cytochrome system. Treatment may accelerate mitochondrial dysfunction, nucleoside reverse transcriptase inhibitors may contribute to muscle wasting. Some typical side effects of HAART such as body change and facial lypoatrophy could be more evident when associated with natural facial changes occurring with aging and modify negatively self perceived body image and relationship capacity. Age was also shown to increase the risk of renal tubular disease in association with tenofovir. Age is one of the major cardio-vascular disease (CVD) risk factors and the inflammatory component may contribute to this increased risk despite HAART efficacy. The risk of myocardial infarctions is increased in older treated HIV+ patients: metabolic abnormalities are more frequent at baseline and the treatment could increase the cumulative risk of CVD.

71-Year-Old Man With Chronic Kidney Failure and Sudden Change of Mental Status

71-year-old man was admitted to the hospital for al- tered mental status. His wife reported that the patient had become progressively confused and had been having visual hallucinations, seeing people and animals that were not really there. These symptoms started about 2 weeks before admission as intermittent episodes. She could not identify any triggering events or temporal pattern for these episodes. In the past 2 days, the patient's symptoms had become more persistent. She added that he had become in- creasingly forgetful in the past year but had had no prob- lem performing simple tasks or taking care of himself. This type of confusion had never occurred previously. The patient had a 12-year history of type 2 diabetes, had undergone coronary artery bypass 3 years previously, had symptomatic peripheral vascular insufficiency, and had stage V chronic kidney disease primarily due to diabetic nephropathy. For the past 10 months, he had been undergo- ing hemodialysis 3 times weekly for 3.5 hours each time via a left arm arteriovenous fistula. He had last undergone dialysis 3 days previously and was due for his scheduled dialysis on the day of admission. Two months before admission, the patient developed critical lower limb ischemia and a nonhealing left foot ul- cer. Multiple vascular interventions failed to restore suffi- cient limb blood flow; a month later, the patient underwent a transmetatarsal amputation. Postoperatively, he devel- oped surgical wound infection, necessitating repeated de- bridement and intravenous vancomycin administration. The patient's medications included stable doses of as- pirin, atenolol, atorvastatin, calcium acetate, insulin, gaba-

Immunoregulatory activity of the nonspecific resistance stimulator ribotan and its inhibiting effect on the liver P450 cytochrome system of mice invaded by Aspiculuris tetraptera

The inhibiting effect of the nonspecific resistance stimulator ribotan on the liver P450 cytochrome system combined with immunoregulatory activity of the drug is established in the model “mouse-A. tetraptera” system. The effect of inhibition depends on dose and regime of using ribotan. A close inverse correlation is found between anti-invasion resistance and activity of the metabolic system of liver microsomes.

Drug Interaction Between Clopidogrel and Proton Pump Inhibitors

Dual antiplatelet therapy with clopidogrel and aspirin has been shown to reduce recurrent cardiac events in patients with acute coronary syndromes or those who have undergone coronary artery stent placement. Clopidogrel, a thienopyridine, is a prodrug that is transformed in vivo to an active metabolite by the cytochrome P450 enzyme system. Due to the increased risk of bleeding in patients on dual antiplatelet therapy, concomitant gastrointestinal ulcer prophylaxis with a proton pump inhibitor (PPI) is frequently prescribed. Data from recent studies show that PPIs, which are extensively metabolized by the cytochrome system, may decrease the antiplatelet activity of clopidogrel. This article reviews the metabolism of various PPIs and existing data regarding the drug-drug interaction between PPIs and clopidogrel.

Cytochrome modulation decreases the risk of cataract: Is the basic hypothesis flawless?

Sir, We have read the article, “Is cytochrome modulation the new frontier for decreasing the risk of cataract?” published in IJP, April 2009[1] with great enthusiasm. The study is based on the hypothesis excess glucose is converted to sorbitol (which can cause cataract) by enzyme aldose reductase using NADPH as a cofactor, and electron transfer from NADPH further depends on the cytochrome P450 system. Thus, it was postulated that by inducing or inhibiting cytochrome one can alter the activity of aldose reductase, formation of sorbitol, and the occurrence of cataract. We feel that this hypothesis is not flawless and would wish to make the following observations in this regard: NADPH is used as a cofactor for aldose reductase and it is also used to transfer electrons in the cytochrome P450 system which then participates in the metabolism of drug/endogenous metabolites.[2] Thus, any reaction that will alter the synthesis of NADPH will only be able to affect the aldose reductase pathway. But, NADPH is biosynthesized by the hexose monophosphate shunt (HMP shunt),[3] (and not by the cytochrome system) and so by modulating cytochrome activity one cannot alter the activity of aldose reductase. The aldose reductase pathway is absent in liver.[3] It therefore appears that the very site where induction of enzymes occur maximally lacks the sorbitol pathway for cytochrome modulation to be able to affect the cataract formation. It has been hypothesized that by simple alteration in the medication (CYP inhibitors instead of CYP inducers) one can reduce the risk of cataract. If we assume that cytochrome modulations alter the activity of aldose reductase through NADPH, then this would mean that enzyme induction will decrease the amount of NADPH which is available to be used as a cofactor by aldose reductase (because more NADPH is now being used in cytochrome pathway due to its induction) and thus decrease the rate of this enzymatic reaction. In other words, it appears that enzyme inducers will decrease the amount of sorbitol formed and vice-versa. If we assume that drugs directly modulate the activity of aldose reductase, then one has to keep in mind that as stated earlier, aldose reductase is absent in liver, where most of diltiazem (about 60%) undergoes first pass metabolism.[4] Direct involvement of drugs with aldose reductase at this site is out of question. Although, besides lens, aldose reductase is present at other sites like kidney, placenta, and seminal vesicles,[3] its presence at these places cannot be responsible for cataract formation. Moreover, the drugs used in this experiment, i.e. pioglitazone and diltiazem, are bound to plasma proteins to an extent of 99% and 80%, respectively.[4] So, it is doubtful if they will accumulate in eye in sufficient quantities to have their effect. The authors have used pioglitazone as an enzyme inducer but doubts have already been raised on its potential to induce CYP3A4.[5,6] Authors have used galactose-rich diet to induce cataract although it has been argued that galactose fed rats are not a good model of diabetes and the subsequent induction of cataract.[7] It has also been pointed out that the use of galactose fed animal models leads to subsequent clinical failure of aldose reductase inhibitors.[7]

ANTIEPILEPTIC DRUGS IN THE TREATMENT OF NEUROPATHIC PAIN: DRUG‐TO‐DRUG INTERACTION IN ELDERLY PEOPLE

To the Editor: Pain is a common complain in elderly people, often linked to neuropathic syndromes that affect old people particularly, such as trigeminal neuralgia, painful diabetic neuropathy, and postherpetic neuralgia.1 The effectiveness of anticonvulsant drugs in the management of neuropathic pain has been proven; for example, carbamazepine has been extensively employed and evaluated for pain relief in trigeminal neuralgia and has received Food and Drug Administration approval for this use.2–4 Nevertheless, carbamazepine has a narrow therapeutic window and has caused, albeit rarely, severe side effects, including hepatic failure, agranulocytosis, aplastic anemia, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In addition, in polymedicated elderly patients, there is a high potential for adverse effects from drug-to-drug interactions, carbamazepine being a powerful inducer of the hepatic P450 cytochrome system. This could lead to reduced effectiveness of the drugs co-prescribed with carbamazepine. A 90-year-old woman was admitted to the hospital with exacerbation of long-standing arterial hypertension. She was also known to have symptomatic facial neuralgia, which had been treated with carbamazepine over many years. During her hospital stay, secondary causes of hypertension, such as pheochromocytoma and renal artery stenosis, were excluded. High systolic blood pressure measurements (range 240–260 mmHg) were noted several times daily despite pentatherapy (calcium channel blocker, loop diuretic, thiazide diuretic, angiotensin II receptor antagonist, and beta-blocker). Left ventricular hypertrophy was diagnosed according to echocardiogram. Other treatments with drugs that are not metabolized by the liver, in this case glyceryl trinitrate and moxonidine, appeared to be more effective. This observation suggested that the treatment resistance of the hypertension might be due to an effect of carbamazepine at the level of the antihypertensive drugs' hepatic metabolism. After discontinuing carbamazepine (replaced by gabapentin) and allowing sufficient time for its elimination, significant improvement in the blood pressure profile was observed; mean arterial blood pressures decreased from 177/64 mmHg (38 measures/24 h) to 157/65 mmHg (17 measures/24 h). Blood pressure measurements greater than 200 mmHg disappeared completely (>10 peaks/24 h previously), allowing the antihypertensive treatment regime to be reduced from five to three drugs. Some months after discharge home, carbamazepine was reintroduced for neurological symptoms, leading again to an uncontrolled elevation in blood pressure and hospital readmission. Carbamazepine has been reported to be associated with arterial hypertension and (more frequently) with exacerbation of preexisting hypertension through its effect on hepatic drug metabolism.5–7 Carbamazepine induces the cytochrome P450 enzymes 3A4, 2C9, and 1A2, which catalyze many antihypertensive drug types, for example, the calcium channel blockers, angiotensin II receptor antagonists, some loop diuretics (torsemide), and some alpha- and beta-blockers. Consequently, the pharmacological effect of these antihypertensive drugs is diminished. The hepatic cytochrome system does not metabolize other blood pressure–lowering molecules (such as angiotensin-converting enzyme (ACE) inhibitors, thiazide diuretics, potassium-sparing diuretics, agonists of alpha-2 central receptors, nitrates, and some beta-blockers (atenolol)), and hence the concomitant use of carbamazepine or other cytochrome P450–inducing drugs (e.g., rifampicin, dexamethasone, phenytoin, phenobarbital, and St. John's wort (Hypericum perforatum) does not affect their pharmacological effect. In addition to antihypertensive agents, cytochrome P450 metabolizes many other drugs, whose effect may also be expected to be compromised in the presence of carbamazepine. In our patient's treatment, cytochrome P450–metabolized drugs, including paracetamol, clopidogrel, omeprazole, zolpidem, and mianserin, were prescribed. The clinical case presented here illustrates the importance of considering potential drug-to-drug interactions whenever an anticipated therapeutic effect is not realized. The phenomenon of induced or exacerbated hypertension by carbamazepine is well known but is rarely mentioned in the geriatric literature, probably because the drug's primary indication is in the treatment of epilepsy, a condition that usually presents in younger patients, who rarely have concomitant hypertension, but carbamazepine has many other indications, such as for bipolar disorder, withdrawal procedures, and neuropathic pain, and its use has become more frequent, including in geriatric populations, in spite of the risk of interactions, or the risk of hepatic, cutaneus, and hematological toxicities. Carbamazepine is consequently not recommended for use in elderly patients, and an alternative treatment should be considered. Gabapentin, alone or in combination with clonazepam, should be tried for neuropathic pain,8,9 and antidepressants (tricyclics), topical anaesthetic agents, opiates, and analgesics could also be considered.10,11 Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this letter. Author Contributions: Emilia Frangos Lordos and Véronique Trombert: preparation of manuscript, acquisition of subject, interpretation of data. Nicole Vogt: revision of manuscript. Jean-Jacques Perrenoud: Revision of manuscript, supervision. Sponsor's Role: None.

High-dose atorvastatin does not negatively influence clinical outcomes among clopidogrel treated acute coronary syndrome patients—A Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) analysis

Clopidogrel is inactive in vitro and is metabolized by hepatic cytochrome P-450-3A4 to produce active metabolites. Unlike pravastatin, atorvastatin is a statin that is subject to metabolism by cytochrome P-450-3A4, and drug-drug interactions with other potent inhibitors of this cytochrome system have been demonstrated. However, the clinical impact of this interaction has created debate. In the PROVE IT-TIMI 22 study, 4162 patients with an acute coronary syndrome within the preceding 10 days were randomly assigned in a 1:1 fashion to pravastatin 40 mg or atorvastatin 80 mg daily. The primary efficacy outcome measure was the time from randomization until the first occurrence of a component of the primary end point: death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization with either percutaneous coronary intervention or coronary artery bypass grafting, or stroke. At 30 days, there was a trend for less occurrence of the primary end point in patients randomized to atorvastatin compared with pravastatin, irrespective of whether they were taking clopidogrel. This becomes significant at 2-year follow-up in clopidogrel-treated patients (21.66 % vs 26.18% P = .0091). There was no evidence of interaction in the clopidogrel/no clopidogrel subgroup for the primary end point (interaction P = .65) or the components of the composite. In conclusion, the beneficial affects of atorvastatin 80 mg in reducing the primary end point at 2 years is independent of coadministration with clopidogrel.

Force microscopy analysis using chemometric tools

In this paper we report the first application of multivariate data analysis techniques to force spectrometry measurement sets to enable the physicochemical assignment of spatially ordered multi-component systems. Principal component analysis (PCA) and hierarchical clustering techniques were used to reveal hidden chemical information within force-distance curves generated by high spatial resolution force microscopy. Two experimental samples were analyzed: (i) a two-component system of cytochrome c proteins on a mica surface, and (ii) a three-component system of avidin protein islands positioned on a gold and glass surface. PCA and hierarchical clustering techniques were used to discriminate the different components of the two-component system, whereas hierarchical clustering was found to be superior for the three-component system. Results were in good agreement with the topography and prior knowledge of the surface patterns. This research represents a formative step towards the combination of force spectrometry with chemometric tools for the high resolution physicochemical investigation of complex biochemical systems.

Levetiracetam

Levetiracetam (LEV) is a broad-spectrum antiepileptic drug that is effective against a variety of seizure types. It is a pyrridoline derivative with a very favourable pharmacokinetic profile: excellent bioavailability, linear kinetics, minimal plasma protein binding and quick achievement of steady state concentrations. It is not metabolized through the P450 hepatic cytochrome system, does not induce its own metabolism and has no clinically relevant drug-drug interactions. It is available as film-coated tablets, liquid formulation for oral ingestion and intravenous concentrated solution. Controlled and open-label studies have shown its efficacy and safety as initial monotherapy and add-on treatment for partial-onset seizures in children and adults, and also as add-on therapy in refractory partial and primary generalized seizures. Its rapid onset of action, lack of drug-drug interactions and availability as an intravenous solution make it an optimal drug to treat epilepsy associated with other medical conditions. Preliminary reports also suggest potential efficacy in refractory status epilepticus, although this is not a registered indication. Levetiracetam is generally well tolerated, and no serious idiosyncratic side effects have been reported so far. Behavioral side effects (hostility up to aggressive behaviour) are not uncommon. Small, uncontrolled studies have suggested potential therapeutic potential in difficult-to-treat dyskinesias in Parkinson's disease, tremors of different etiologies, migraine prophylaxis and mood disorders. This needs to be confirmed in larger, controlled studies.

Cloning and Characterization of Ferredoxin and Ferredoxin-NADP+ Reductase from Human Malaria Parasite

The human malaria parasite (Plasmodium falciparum) possesses a plastid-derived organelle called the apicoplast, which is believed to employ metabolisms crucial for the parasite's survival. We cloned and studied the biochemical properties of plant-type ferredoxin (Fd) and Fd-NADP+ reductase (FNR), a redox system that potentially supplies reducing power to Fd-dependent metabolic pathways in malaria parasite apicoplasts. The recombinant P. falciparum Fd and FNR proteins were produced by synthetic genes with altered codon usages preferred in Escherichia coli. The redox potential of the Fd was shown to be considerably more positive than those of leaf-type and root-type Fds from plants, which is favourable for a presumed direction of electron flow from catabolically generated NADPH to Fd in the apicoplast. The backbone structure of P. falciparum Fd, as solved by X-ray crystallography, closely resembles those of Fds from plants, and the surface-charge distribution shows several acidic regions in common with plant Fds and some basic regions unique to this Fd. P. falciparum FNR was able to transfer electrons selectively to P. falciparum Fd in a reconstituted system of NADPH-dependent cytochrome c reduction. These results indicate that an NADPH-FNR-Fd cascade is operative in the apicoplast of human malaria parasites.

The pharmacological importance of cytochrome CYP3A4 in the palliation of symptoms: review and recommendations for avoiding adverse drug interactions

Adverse drug interactions are major causes of morbidity, hospitalizations, and mortality. The greatest risk of drug interactions occurs through in the cytochrome system. CYP3A4, the most prevalent cytochrome, accounts for 30-50% of drugs metabolized through type I enzymes. Palliative patients received medications for symptoms and co-morbidities, many of which are substrate, inhibitors, or promoters of CYP3A4 activity and expression. A literature review on CYP3A4 was performed pertinent to palliative medicine. In this state of the art review, we discuss the CYP3A4 genetics, and kinetics and common medications, which are substrates or inhibitor/promoters of CYP3A4. We made some recommendations for drug choices to avoid clinically important drug interaction.

Lipid Lowering Inefficacy of High-dose Statin Therapy Due to Concurrent Use of Phenytoin

HMG-CoA reductase inhibitors ("statins") are the most commonly prescribed lipid lowering agents. Most of the statins are metabolized by the CYP450 cytochrome system. A number of medications either induce or inhibit this system which leads to changes in the bioavailability of the statins and the potential for either an increase in adverse effects or reduction in efficacy. Phenytoin induces the CYP3A4 isoform of the CYP450 system and can reduce the bioavailability, and thus the efficacy of the statins metabolized by this enzyme, including atorvastatin and lovastatin. A case of a patient on multiple lipid-lowering medications, including high-dose atorvastatin whose LDL cholesterol improved significantly after discontinuation of phenytoin is presented, and a review of the literature for similar cases is discussed.