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Articles
Pharmacogenetics and enzyme induction/
inhibition properties of antiepileptic drugs
Abstract-One of the major differences between the older antiepileptic drugs (AEDs) and the newer AEDs is the potential
of the older AEDs for significant interactions with other medications. Many of the drug- drug interactions involving the
older AEDs are reciprocal, i.e., both drugs affect each other. In contrast, the newer AEDs have either no or limited drug
interaction potential. Despite our extensive understanding of and our ability to predict drug- drug interactions, serious
drug interactions still occur. More than 30% of all new seizures occur in the elderly, and because this population may be
taking a variety of other medications the addition of an AED can have profound impact on these other therapies. In
women, the use of enzyme-inducing AEDs can cause significant alterations of sex hormones and can decrease the efficacy
of oral contraceptives. In children and adults, the use of enzyme inducers may result in long-term endocrine effects,
including bone loss and lipid, thyroid, and sex hormone abnormalities. Phenytoin and phenobarbital are metabolized by
cytochrome P450 isozymes, with activity dependent on genetic polymorphism (CYP2C9, CYP2C19). The dosing of the
newer AEDs is not affected by genetic polymorphism. The decreased induction and inhibition effects and the lack of
significant genetic polymorphism of the newer AEDs allow increased ease of use and perhaps greater safety, especially for
patients taking multiple medications.
One of the major differences between the "traditional" the effect of the older AEDs on the metabolism of en- or older antiepileptic drugs (AEDs) and the newer dogenous substances is often underappreciated.
AEDs is in the potential of the older AEDs for signifi- The function of the metabolic enzymes involved in cant interactions with other medications. In general, drug metabolism is twofold: the detoxification of ex- the older AEDs are broad-spectrum inducers (pheno- ogenous compounds, such as drugs, and the metabo- barbital, primidone, phenytoin, and carbamazepine), lism of endogenous compounds, such as steroids. For whereas valproic acid is an inhibitor, of metabolic en- the AEDs, metabolic reactions are catalyzed predom- zymes. Many of the drug- drug interactions involving inantly by the cytochrome P450 (CYP) and UDP- older AEDs are reciprocal, i.e., each drug affects the glucuronosyltransferase (UGT) enzymes. CYP450 other. In contrast, the newer AEDs have either no or limited drug interaction potential. In a recent Depart- isozymes divided among three major families (CYP1, ment of Veterans Affairs cooperative study of seizures CYP2, and CYP3). Seven primary isozymes are in-volved in the hepatic metabolism of most drugs: in the elderly, Ramsay et al.1 found that the mean number of prescription medications per patient was 6.7 (range 0 to 15). With more than 30% of all new seizures isozyme, CYP3A4, which accounts for approximately occurring in the elderly, the addition of an AED can 30% of the total hepatic CYP,2 has the broadest sub- have a profound impact on other therapies that may be strate specificity and is involved in the metabolism of concurrently prescribed. In women, use of enzyme- more than 50% of all drugs.3 The UGTs are a group inducing AEDs can lead to significant alterations of sex of 16 separate isozymes consisting of two major sub- hormones and can decrease the efficacy of oral contra- families, UGT1 and UGT2, which are responsible for ceptives. In children and adults, the use of enzyme the metabolism of a wide variety of endogenous sub- inducers may potentially result in long-term endocrine strates, including steroids and bile acids, as well as effects, including bone loss and lipid, thyroid, and sex drugs.4,5 Recent knowledge of the specific CYP hormone abnormalities. Despite our extensive under- isozymes involved in the metabolism of AEDs facili- standing of drug interactions and our ability to predict tates prediction of potentially inductive and inhibi- them, serious drug interactions still occur. In addition, tory interactions. Research that would facilitate the From the Department of Pharmacy, University of Washington, Seattle, Washington.
Publication of this supplement was supported by an unrestricted educational grant from GlaxoSmithKline. The sponsor has provided G.A. with anhonorarium for her participation in this project. She has also received other honoraria from the sponsor during her career.
Address correspondence and reprint requests to Dr. Gail D. Anderson, Department of Pharmacy, Box 357630,University of Washington, Seattle, WA 98195;e-mail: gaila@u.washington.edu Copyright 2004 by AAN Enterprises, Inc.
Table 1 Induction and inhibition effects of the traditional AEDs
and the potential for an increased pharmacologic re- sponse. Valproic acid is a broad-spectrum metabolicinhibitor, inhibiting CYP2C9 (phenytoin and pheno- barbital), epoxide hydrolase (carbamazepine), and sev- eral UGTs (see table 1). Valproic acid is a potent inhibitor of UGT-dependent metabolism of lamotrigine (UGT1A4),7 zidovudine (UGT2B7),8 and lorazepam [UGT isozyme(s) unknown].9 There have been recent reports of coma induced by a combination of lorazepamand valproic acid10 and of severe anemia secondary to treatment with valproic acid and zidovudine.11 The macrolide antibiotics are also potent inhibitors of CYP3A4-catalyzed metabolism of carbamazepine.
AED ϭ antiepileptic drug; CYP ϭ cytochrome P450 isozyme; Many case reports of interactions between carbamaz- epine and macrolide antibiotics have been published,one with troleandomycin12 as early as 1977 and several prediction of drug interactions involving specific others with erythromycin13,14 and clarithromycin15 dur- ing the 1980s. Despite extensive literature establishingthe serious clinical toxicity that can result from eleva- Hepatic induction.
tions in carbamazepine plasma concentrations with usually the result of an increase in the amount of this combination, case reports were still being pub- enzyme protein. In most cases, enzyme induction lished more than 10 years later.16,17 These examples leads to an increase in the rate of metabolism of the serve to emphasize the clinical significance and poten- affected drug, with a consequent decrease in the se- tial problems of drug interactions, even when these rum concentration of the parent drug and possibly a effects are known and predictable. Of the newer AEDs, loss of clinical efficacy. The older AEDs, including topiramate18 and oxcarbazepine19 selectively inhibit phenobarbital, primidone, phenytoin, and carbamaz- CYP2C19 in vitro. Common substrates of CYP2C19 epine, have significant enzyme-inducing properties include phenytoin, phenobarbital (minor), diazepam, (table 1). In general, they induce a wide range of the proton pump inhibitors (omeprazole, lansoprazole, CYP450 isozymes, including CYP1A2, CYP2A6, and pantoprazole), and antidepressants (citalopram, CYP2B, CYP2C, and CYP3A, as well as the UGT fluoxetine, and sertraline). Only the drug interactions isozymes. Many of the newer AEDs, such as gaba- with phenobarbital and phenytoin have been clinically pentin, levetiracetam, tiagabine, and zonisamide, ei- ther have no induction effects or induce only selectedenzymes (table 2).
Interactions with exogenously administered
drugs.
An expert panel, including physicians, clin- Hepatic inhibition.
ical pharmacists, and an expert on drug- drug inter- usually occurs because of competition at the active site actions (DDIs), identified 56 DDIs.20 The interactions and leads to a decrease in the rate of metabolism of the were ranked on a scale of 1 to 10 in which 10 was affected drug.6 Clinically, this is associated with an most serious and any DDI Ն8 was considered seri- increased plasma concentration of the affected drug ous. The rankings ranged from 1 to 9.2, with a meanrating of 6.6. Of the 56 DDIs listed, three involvedAEDs: carbamazepine and propoxyphene (8.0), car- Table 2 Induction and inhibition effects of the newer AEDs on
bamazepine and macrolide antibiotics (7.6), and phe- nytoin and fluoxetine or fluvoxamine (7.6). In all three cases, the effect on the AED of enzyme inhibi-tion by another commonly used drug resulted in seri- ous drug interactions. This information is critical because health-care providers often prescribe the non-AED drugs to patients who have been prescribedan AED by another physician.
Hepatic enzyme induction by the older AEDs pro- duces major effects on extensively metabolized drugs (Ͼ75% metabolized) with a low therapeutic index.
For the drugs listed in table 3, the addition or dis- continuation of an inducer could result in loss ofefficacy or increased toxicity if plasma concentra- tions are not adjusted.21 Dosage adjustments of ap- proximately 50% to 100% may be necessary and require careful clinical monitoring. The effect of tak- ϭ antiepileptic drug; CYP ϭ cytochrome P450 isozyme; ing the older AEDs in addition to oral contraceptives November 2004
Table 3 Drugs with which addition or discontinuation of a hepatic enzyme inducer could cause clinically significant effects21
Amitriptyline, amoxapine, clomipramine, desipramine, doxepine, imipramine, nortriptyline, Carbamazepine, ethosuximide, felbamate, lamotrigine, phenytoin, tiagabine, topiramate, valproic Itraconazole, ketoconazole, mebendazole, voriconazole Clozapine, haloperidol, risperidone, quetiapine Amprenavir, atazanavir, delavirdine, indinavir, nelfinavir, ritonavir, saquinavir, zidovudine Alprazolam, clonazepam, diazepam, lorazepam, midazolam, triazolam Amlodipine, bepridil, diltiazem, felodipine, isradipine, nisoldipine, nicardipine, nifedipine, Amiodarone, digoxin, disopyramide, procainamide, propranolol, quinidine Cortisone, betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, Conjugated estrogens, ethinyl estradiol, levonorgestrel, norethindrone HMG-CoA ϭ 3-hydroxy-3-methylglutaryl coenzyme A.
(OCs) is a well-known example of a clinically signifi- the decreased propensity of the newer AEDs for drug cant DDI. OCs are widely used by women of child- interactions suggests that they may have less effect bearing age. CYP3A4 is involved in the metabolism of both endogenous and exogenously administered estro- gens and progesterones. The ability of some AEDs to lepsy have reduced fertility and suffer from hypo- induce CYP3A4 results in increased clearance and cor- responding decreased plasma levels of the estrogen population.27-29 A larger number of women with epi- component and also of the progestational component of lepsy have anovulatory cycles compared with control the OCs. Phenytoin, phenobarbital, primidone (via subjects.30,31 Because reproductive endocrine disor- phenobarbital), and carbamazepine induce CYP3A4. Of ders are associated with temporal lobe epilepsy32 and the new AEDs, topiramate, felbamate, and oxcarbaz- primarily generalized epilepsy,33 it is difficult to de- epine are weak inducers of CYP3A4. Topiramate de- termine the role of AEDs. The enzyme-inducing creases ethinyl estradiol levels only at higher doses AEDs increase the concentration of sex hormone- (Ն400 mg/day),22,23 consistent with studies demonstrat- binding globulin (SHBG), resulting in decreased bio- ing a dose-dependent induction of CYP3A4.24 Valproic activity of estradiol and testosterone.34,35 Valproic acid, ethosuximide, lamotrigine, gabapentin, tiagabine, acid is a broad-spectrum inhibitor of UGTs, includ- and probably zonisamide do not alter the efficacy of ing UGT2B15, which is involved in androgen and es- OCs in women taking these AEDs concurrently. There trogen metabolism.36 Isoja¨rvi et al.37 found that has been a recent report of a reciprocal interaction valproic acid was associated with an increased inci- whereby decreased plasma concentrations of lam- dence of polycystic ovaries and hyperandrogenism with otrigine were found when this AED was used in combi- menstrual disturbances. Women taking valproic acid had elevated plasma testosterone and dehydroepi-androsterone sulfate (DHEAS) concentrations and a Interactions with endogenous substances.
trend toward a decreased estradiol concentration.
tients with epilepsy experience a wide variety of When female patients with either polycystic ovaries or endocrine-related problems affecting pituitary, adre- hyperandrogenism were switched to lamotrigine, the nal, thyroid, bone, and sexual function. Both the dis- total number of polycystic ovaries, body mass index, ease state (epilepsy) and the drug therapy have been and fasting serum insulin and testosterone concentra- implicated. Unfortunately, there is little or no infor- tions all declined significantly.38 In men with epilepsy, mation regarding the incidence of endocrine disor- valproic acid was also associated with increased serum ders or the effect on sexual or reproductive function androstenedione concentrations.39 Replacing carbamaz- with the second-generation AEDs. Because many of epine with oxcarbazepine in male patients resulted in a the endocrine effects may be due to the impact of the decrease in SHBG concentrations and an increase in AED on the metabolism of endogenous hormones, DHEAS concentrations, with no change in serum free November 2004
and total testosterone, follicle-stimulating hormone, lu- ble for the conjugation of bilirubin. Bilirubin glucu- teinizing hormone, or prolactin, suggesting that oxcar- ronidation activity is significantly increased by bazepine may have less effect than carbamazepine.40 phenobarbital-type inducers.53 Therefore, induction The endocrine effects of oxcarbazepine did not occur with doses Ͻ900 mg/day in a group of men with epilep- inducing AEDs (carbamazepine, phenytoin, and phe- sy.39 In addition, as reported in a review article by nobarbital) is also consistent with metabolism of T4 Morrell,26 lamotrigine and gabapentin do not appear to by UGT1A2. Recent studies have found that T is not alter SHBG or adrenal or gonadal steroids significantly glucuronidated in the human liver or kidney, suggesting that the metabolism of T is pri- can also increase the risk for serious bone fractures.
marily due to sulfation and deiodination.52 The hepatic enzyme-inducing properties of AEDs Maximal decreases in thyroid hormones (T and T ) have been shown to increase the metabolism of ac- were found after 14 days of treatment with carbamaz- tive vitamin D to inactive metabolites. Decreased vi- epine (400 mg/day) in healthy subjects. This time tamin D may then lead to decreased calcium course of effect is consistent with the time course of the absorption in the gastrointestinal tract.41 However, enzyme-inducing properties of carbamazepine. A re- decreased bone mineral density (BMD) occurs with cent study54 evaluated thyroid function in girls (aged 8 normal vitamin D metabolism in some patients re- to 18 years) with epilepsy taking carbamazepine (N ϭ ceiving the older AEDs, suggesting that the older 19), oxcarbazepine (N ϭ 18), or valproic acid (N ϭ 41).
AEDs may also have a direct effect on bone cells.42 In Consistent with other studies that included male and a prospective study evaluating the risk for hip frac- female patients, valproic acid did not affect thyroid tures in women 65 years or older, women currently function.55 Carbamazepine and oxcarbazepine resulted taking enzyme-inducing AEDs had a twofold higher in equally low serum thyroid hormone (T and free risk for hip fracture.43 A retrospective analysis of thyroxin) concentrations. Thyroid function normalized BMD studies in patients with epilepsy receiving after withdrawal of therapy.54 In contrast to the study enzyme-inducing AEDs found that lower BMD was in girls, when carbamazepine was replaced with oxcar- associated with low body mass index and longer du- bazepine in 12 male patients with epilepsy (aged 21 to ration of AED use.44 Patients with epilepsy receiving 40 years), free and total thyroxin levels increased to phenobarbital, phenytoin, and carbamazepine, but normal.56 Therefore, the effect of the older AEDs may not valproic acid, have hypocalcemia, hypophos- be related to their UGT enzyme-inducing properties. Of phatemia, increased serum alkaline phosphatase ac- the newer agents, both oxcarbazepine and lamotrigine tivity and parathyroid hormone, and decreased are also inducers of the UGT enzymes, although both active vitamin D serum levels. Duration of therapy induce UGT to a lesser degree than the older AEDs with phenytoin and/or carbamazepine correlated and the specificity of the induction is not known. Ex- with the BMD at the lumbar spine and femoral neck cept for oxcarbazepine, no long-term studies on the ef- region in 59 patients.45 Valproic acid, which is not an fect of any of the other new AEDs on thyroid hormones enzyme inducer, was also associated with decreased have been published. If the primary effect on thyroid BMD in children.46,47 These studies highlight the dif- hormone concentrations is due to induction of UGT1A2 ficulty of attributing disturbances in bone metabo- metabolism of T , then we would expect the other lism solely to the enzyme-inducing effects of AEDs.
newer AEDs to be similar to valproic acid in their lack There is also little or no information on the effects of the new AEDs on bone function, although one study found no significant reduction in calcium or markers linked elevated total cholesterol (TC) and low- of bone resorption or bone formation in women density lipoprotein cholesterol (LDL-C) levels and re- duced high-density lipoprotein cholesterol (HDL-C) levels to the development of coronary artery disease oin, and phenobarbital affect thyroid function, primar- in men and women. Epidemiologic studies have also ily by decreasing thyroid hormone concentrations.49,50 It demonstrated that mortality due to atherosclerosis- has been hypothesized that the enzyme-inducing prop- related heart disease is lower among patients with erties of older AEDs are responsible for increasing the epilepsy treated with AEDs than in the general pop- glucuronide metabolism of the thyroid hormones.51 ulation.57 The increase in HDL-C levels associated The thyroid gland releases the hormones tetraiodo- with phenytoin, carbamazepine, and phenobarbital thyronine (thyroxine or T ) and tri-iodothyronine has been suggested as a positive effect.58 As with the (T ). Regulation of T and T levels is under strict other endocrine effects of the AEDs, the hepatic control of thyroid-stimulating hormone (TSH), which enzyme-inducing properties of the first-generation is influenced by negative feedback regulation by the AEDs may be a factor in these lipid effects. There is a thyroid hormone levels. T is deiodinated to produce correlation between the HDL-C concentration and he- patic microsomal enzyme activity and CYP450 content glucuronidation and sulfation. UGT1A2 is the in liver biopsy specimens.59 In contrast, an increase in isozyme primarily responsible for conjugating T in TC and LDL-C levels after AED therapy suggests a the liver, with UGT1A9 also involved but to a lesser possible negative cardiovascular effect. Of the first- degree.52 UGT1A2 is the primary isozyme responsi- generation AEDs, only valproic acid does not increase November 2004
HDL-C. However, valproic acid does decrease TC and (CYP2C19*1/*2 or *1/*3) than in 52 with the homozy- LDL-C.58,60 A study of a large group of children with gous wild-type.66,67 Odani et al.67 found that the maxi- epilepsy61 found that TC and LDL-C levels were high in children receiving phenobarbital (mean age 8.1 Ϯ patients with epilepsy who were heterozygous for 3.5 years) or carbamazepine (11.4 Ϯ 2.7 years) and low CYP2C9*1/*2 compared with homozygous wild-type in those treated with valproic acid (9.1 Ϯ 3.5 years).
(CYP2C*1/*1). The effect of the CYP2C9 mutation was Mean apolipoprotein A-1 levels were low in all treated significantly greater than was found for the CYP2C19 groups. The authors proposed that there may be an increased risk for atherosclerosis-related disease, par- patients with the CYP2C19 mutations (*2 or *3) com- ticularly in children treated with carbamazepine or pared with those who had homozygous wild-type *1/*1.
phenobarbital. No information is available about the The fraction of phenobarbital that is eliminated by relationship between lipid function and the newer CYP2C9- or CYP2C19-dependent oxidation is signif- AEDs. Given the decreased hepatic enzyme induction icantly smaller (ϳ25%) than for phenytoin. Pheno- of the second-generation AEDs, it is possible that the barbital is eliminated by a combination of renal effects on lipids may be significantly less excretion of unchanged drug (25%), N-glucoside for-mation (25%), and CYP450 oxidation. Therefore, the Pharmacogenetics of AEDs.
effect of polymorphism is significantly less than that metabolic enzymes is dependent on genetic, physio- found with phenytoin. Mamiya et al.66 genotyped logic, and environmental effects. Genetic polymor- CYP2C19 in 74 patients receiving phenobarbital.
phism in the expression of N-acetyltransferases Phenobarbital total plasma clearance was only 19% (NAT2), CYP1A2, CYP2C9, CYP2C19, and CYP2D6 less in patients with CYP2C19*2/*2 and *2/*3 than has been identified. Poor metabolizers are homozy- gous for the mutant gene. Extensive metabolizers Of the new AEDs, only zonisamide is eliminated are either homozygous or heterozygous for the wild- by a polymorphic metabolic pathway, NAT2.68 Ap- type gene, with heterozygous carriers having inter- proximately 50% of whites and 10% of Asians or mediate metabolic activity. Ultrametabolizers have blacks are poor (slow) acetylators (i.e., they are ho- multiple copies of the gene; however, this has been mozygous carriers of NAT2 mutant alleles). Only described only for the CYP2D6 polymorphism. There 15% of zonisamide is metabolized by NAT2. There- is a large interethnic variability in the proportion of fore, the acetylation pathway will effect only a frac- poor metabolizers and ultrametabolizers. Of the tion of the total elimination of zonisamide and AEDs, only phenytoin and phenobarbital are subject should not affect the pharmacokinetics or dosing.
to genetic CYP450 polymorphism. Both are metabo-lized by CYP2C9 and CYP2C19. The CYP2C en- Conclusion.
zymes account for approximately 20% of the CYP450 tion effects and the lack of significant genetic poly- in the liver. CYP2C9 is responsible for the metabo- morphism of the newer AEDs allow increased ease of lism of S-warfarin (the active isomer of racemic war- use, especially for patients taking multiple medica- farin), phenytoin, tolbutamide, and several of the tions. Very little is yet known about the long-term nonsteroidal anti-inflammatory drugs (diclofenac, pi- effects, if any, of the newer AEDs on the endocrine roxicam, and ibuprofen). Of the identified mutant system. The decreased propensity of the newer AEDs alleles of CYP2C9, CYP2C9*2 and CYP2C9*3 have for drug interactions suggests that they will have 70% and 3% to 5% enzymatic activity compared with fewer endocrine effects; however, more research is the wild-type, CYP2C9*1. Approximately 40% of the white and 5% of the Asian or black populations areheterozygous for either CYP2C9*2 or CYP2C9*3 and References
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