Review

Introduction

Despite its profound progress, modern pharmacotherapy still faces many challenges such as adverse drug reactions, sometimes serious or even lethal, and nonresponse to standard therapy. The observed prominent variability in individual response to pharmacotherapy, in part, depends on well-known factors easily assessable, like age, sex, weight, liver and renal function, co-medication, heterogeneity in the disease, nutritional state or smoking. Furthermore, inherited variants in drug-metabolizing enzymes (DMEs), transporters, receptors and molecules of signal transduction cascades may have a major impact on drug response.

Pharmacogenetics/pharmacogenomics tries to define the influence of genetic factors on drug efficacy and adverse drug reactions. Whereas pharmacogenetics is focused on pharmacological consequences of a single gene mutation, pharmacogenomics tries to simultaneously consider numerous genes and their mutual interaction. A major progress in pharmacogenetics/pharmacogenomics has been possible thanks to the genetic revolution with the human genome project and the development of modern technologies in genetic testing. It has been expected that personalized medicine considering patients' individual genetic profile would soon be introduced into clinical practice. Since variation in drug concentrations resulting from respective genetic polymorphisms in DMEs could be directly implemented into dose adjustments, genotyping for DMEs seems to be the closest to incorporation into clinical practice.¹ In contrast, genotyping for drug transporters and receptors cannot be recommended as a tool for improvement of drug therapy in clinical practice at present, and respective gene tests are not ready for clinical use.²

The importance of genetic variants of DMEs to explain interindividual differences in drug concentrations and corresponding pharmacodynamic effects has been recognized about 50 years ago.³ Early examples include the metabolism of succinylcholine, isoniazid, debrisoquine or sparteine. Today, the functional consequences of genetic polymorphisms have been examined for most DMEs. Variants leading to complete deficiency of enzyme activity as well as those with reduced or increased activity compared to the wild-type alleles have been reported. Thus, for a fraction of drugs, it would be desirable to consider individual activity of respective DMEs as the basis for optimizing therapy.

The objective of this article is to critically review the data on genetic polymorphisms of DMEs with emphasis on clinical relevance and the level of evidence, in order to define situations where genotyping or phenotyping might be beneficial for drug safety or therapeutic outcome. The data on genetic polymorphisms in DMEs are presented for several clinically important drug therapies of major medical conditions (Table 1) and, at the end of each chapter, a short statement is made on the potential benefit of geno-/phenotyping in this respective field.

Table 1 - Summary of the reviewed medical conditions, respective medicinal treatments and involved genetically polymorphic drug-metabolizing enzymes.

Full table

Depression

Pharmacotherapy of depression, one of the major psychiatric disorders, is characterized by long duration of drug therapy, relatively narrow therapeutic index and poor individual prediction of therapeutic response. According to the evidence, about 30% of all depression patients do not respond sufficiently to the first antidepressant drug given.^{4, 5} Failure to respond to antidepressant drug therapy as well as intolerable side effects not only determine personal suffering of individuals and their families, but also impose considerable costs on society. At present, there is no possibility to reliably predict the individual's response before onset of a certain drug treatment.

Tricyclic antidepressants

Many tricyclic antidepressants undergo similar biotransformation in the liver with CYP2D6 catalyzing hydroxylation or demethylation reactions.⁶ CYP2D6 is characterized by a high interindividual variability in catalytic activity mainly caused by genetic polymorphisms.⁷ The respective phenotype determined by CYP2D6 genotype is predicted by the number of functional CYP2D6 alleles, so that the presence of two, one or no functional CYP2D6-gene copies results in phenotype of, respectively, rapid or extensive metabolizer (EM), intermediate metabolizer (IM) and slow or poor metabolizer (PM).^{8, 9} Furthermore, inheritance of three or more functional alleles by gene duplication or gene amplification determines the ultrafast metabolizer (UM) phenotype showing higher-than-average enzymatic activity.^{9, 10} (The situation is even more complex with the existence of functional but low-activity alleles such as CYP2D6*10 and influences other than genotype on CYP2D6 activity, but as data on therapeutic consequences of these factors is very limited, this is not considered here.^{8, 9, 10})

PMs of CYP2D6 have largely (50% or more) decreased clearance values which was reported for amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, doxepin and trimipramine.¹¹

Intuitively, one might expect that individuals to whom tricyclic antidepressants are prescribed could benefit from CYP2D6 genotyping if the dose is adjusted for the group of PMs and UMs of CYP2D6.

In addition to CYP2D6, another highly polymorphic DME, CYP2C19, also takes part in biotransformation of some tricyclic antidepressants like amitriptyline, imipramine and clomipramine.¹² However, a possible impact of CYP2C19 polymorphism on the pharmacokinetics of tricyclic antidepressants is by far not so well documented as that of CYP2D6.

Selective serotonin re-uptake inhibitors (SSRIs)

Some selective serotonin re-uptake inhibitors such as fluoxetine, fluvoxamine and paroxetine are potent inhibitors of CYP2D6 activity. Therefore, multiple dosing causes auto-inhibition of CYP2D6 and conversion from extensive to slow metabolizer phenotype and from ultrafast to extensive metabolism was described.^{13, 14} In the case of fluvoxamine, differences in concentration–time curves (AUCs) between CYP2D6 genotypes were described after single doses,^{15, 16} whereas multiple doses result in similar AUCs in PMs and in EMs indicating a strong inhibitory effect on CYP2D6 in EMs.¹⁷

For fluoxetine undergoing enantioselective metabolism toward the S-enantiomer, impaired demethylation of S-fluoxetine in CYP2D6 PMs was observed.¹⁸ However, since the metabolite desmethylfluoxetine is also an active antidepressant, no clinical implications should be expected with regard to variable metabolism of fluoxetine as the parent drug.¹⁹ For paroxetine, although it is also a CYP2D6 inhibitor, twofold higher AUCs of the drug were observed in CYP2D6 PMs than in EMs after multiple doses,²⁰ whereas and in another study, one UM carrying at least three functional CYP2D6 gene copies had undetectable drug concentrations.¹³ In contrast, no influences of CYP2D6 polymorphisms on pharmacokinetic parameters of sertraline and citalopram have been described.

Thus, in conclusion, within the group of SSRIs, CYP inhibition poses a problem for drug interaction, but the CYP2D6 gene polymorphism has less effect, and CYP2D6-based dose adjustments do not seem to be useful for this group of antidepressants (with the exception of paroxetine).

Other antidepressants

For mirtazapine, it could be shown that CYP2D6 genotype had a significant influence on the variability in the plasma concentration, however, when comparing UMs to EMs, the magnitude of concentration differences was only moderate.²¹

CYP2D6 is responsible for the transformation of venlafaxine to the equipotent O-desmethyl-venlafaxine.^{22, 23, 24} Thus, for mirtazapine and venlafaxine, CYP2D6 influence on pharmacokinetics is only small and genotyping with subsequent dose adjustments does not seem to be of large benefit.

The existing data on effects of CYP2D6 polymorphisms on metabolism of the tetracyclic antidepressant maprotiline is contradictory.^{25, 26}

Finally, CYP2D6 polymorphism seems to have no major influence on metabolism of nefazodone, moclobemide, reboxetine and trazodone.^{27, 28, 29, 30, 31, 32, 33}

Possible clinical implications

The question whether the differences in pharmacokinetic parameters caused by genetic polymorphisms in DMEs really impact the outcome of antidepressant treatment has been studied in some observational studies. In a German study evaluating the effect of CYP2D6 genotype on treatment with CYP2D6-dependent antidepressants, PMs and UMs were significantly overrepresented as compared to the control population, respectively, in the group of patients suffering from adverse drug reactions (fourfold) and nonresponders (fivefold).³⁴ At the same time, Grasmader et al.³⁵ did not find any influence of CYP2D6 and CYP2C19 genotype on antidepressant drug response, although the incidence of relevant side effects tended to be higher in PMs of CYP2D6. A high risk for cardiotoxic events and severe arrhythmia was reported in four patients treated with venlafaxine admitted to a cardiologic unit who all were CYP2D6 PMs.³⁶ Furthermore, a prospective 1-year clinical study of 100 psychiatric inpatients suggested a trend toward longer duration of hospital stay and higher treatment costs in UMs and PMs of CYP2D6.³⁷

In conclusion, for treatment with antidepressants, there is extended evidence mainly for CYP2D6 and, to a lower extent, for CYP2C19 polymorphisms affecting pharmacokinetics of several antidepressants and possibly affecting therapeutic outcome and adverse drug effects. The usefulness of genotyping procedures in depressed patients, however, has not been confirmed in prospective clinical trials; therefore, currently this approach is limited to a few enthusiastic hospitals, such as the Mayo Clinic, and to some patients with adverse or no therapeutic effects. However, with the recent approval of pharmacogenetic tests for CYP2D6 and CYP2C19 by the Food and Drug Administration (FDA), a more extensive application of DME-based personalized therapy in depression may be expected. Tentatively, before more results of clinical studies are available, dose adjustments according to pharmacokinetic differences between genotypes in order to achieve a more uniform drug exposure may be used.³⁸

Cardiovascular diseases

Cardiovascular diseases are the major cause of morbidity and mortality in developed countries. For a couple of drugs used in the therapy of cardiovascular diseases, like some -blockers and sartans, clinical implications resulting from genetic polymorphisms in DMEs are discussed.

-Blockers

For metoprolol, one of the most often prescribed -blockers, the role of CYP2D6 genetic polymorphisms in its pharmacokinetics is well established. CYP2D6 catalyzes O-demethylation and, even more specifically, -hydroxylation of the drug.³⁹ Metabolism by CYP2D6 showed a slight preference for the (R)-enantiomer over the pharmacologically active (S)-enantiomer⁴⁰ but in both enantiomers, there is a substantial difference between CYP2D6 EMs and PMs.^{41, 42} Not only metoprolol plasma concentrations but also the effects on heart rate correlated significantly with CYP2D6 metabolic phenotype.^{39, 43} Kirchheiner et al.⁴⁴ described the effects of CYP2D6 genotype on pharmacokinetics of metoprolol and heart rate. In UMs carrying the CYP2D6 gene duplication, total clearance of metoprolol was about 100% higher compared with EMs (367 versus 168 l/h). These pharmacokinetic differences were reflected in pharmacodynamics so that the reduction of exercise-induced heart rate by metoprolol in the UM group was only about half of that observed in the EMs.

Another -blocker, the racemate carvedilol, which was the first to be approved as adjunctive therapy in the treatment of heart failure, is known to be stereoselectively metabolized by cytochrome P450 enzymes.⁴⁵ Whereas 1-antagonism is primarily conferred by the S-enantiomer of carvedilol, the R-isoform is responsible for 1-blockade.⁴⁶ CYP2D6 polymorphism has been shown to alter the disposition of carvedilol enantiomers. PMs demonstrated an impaired clearance of R-carvedilol, thus being affected by a more pronounced 1-blockade which might outweigh the beneficial 1-blocking effects.⁴⁷ Hence, CYP2D6 genotyping might predict therapeutic outcome in patients with chronic heart failure treated with carvedilol. However, the inhibition of CYP2D6 metabolism by administration of fluoxetine in EMs led to significant changes in plasma pharmacokinetics in favor of the R-enantiomer without any effects on blood pressure and heart rate which casts doubt on the clinical significance of the CYP2D6 genotype for the treatment with carvedilol in antihypertensive therapy.⁴⁸

In summary, in our opinion, CYP2D6 genotyping might be beneficial, if at all, for long-term treatment with metoprolol in indications such as heart failure or in post-myocardial infarction patients where no surrogate parameter such as blood pressure is available to predict long-term efficacy.

AT₁ receptor antagonists (sartans)

AT₁ (angiotensin II type 1) receptor antagonists, which are also used in the treatment of hypertension and congestive heart failure, are metabolized with involvement of the polymorphic cytochrome P450 enzyme CYP2C9. CYP2C9*2 and CYP2C9*3 are the clinically best-investigated alleles connected with impaired intrinsic enzymatic activity, however, the latter, which results in changes in the substrate binding region of CYP2C9, seems to be of primary importance.⁴⁹

Losartan, a potent antagonist of AT₁, is metabolized via CYP2C9 and CYP3A4 to its active metabolite, E-3174.⁵⁰ McCrea et al.⁵¹ described a case of a patient showing a minimal conversion of losartan to its active metabolite who was diagnosed as phenotypic PM for CYP2C9 and carrier of the CYP2C9*3 variant allele. Likewise, in a study of 39 healthy volunteers, the CYP2C9*3 allele was shown to be associated with decreased formation of E-3174.⁵² On the other hand, Lee et al.⁵³ observed no differences in the pharmacokinetics of losartan and its active metabolite between subjects with the genotype of CYP2C9*1/*2 and *1/*3 and those expressing *1/*1. The influence of CYP2C9 polymorphism on pharmacokinetics or the dynamics of other AT₁ receptor antagonists like irbesartan or candesartan has also been explored. Both drugs are metabolized by CYP2C9 but in contrast to the pro-drug losartan, they are the active forms. In patients with the CYP2C9*1/*2 genotype, there was a stronger reduction of the diastolic blood pressure (14.4%) upon therapy with irbesartan as compared to wild-type carriers (7.5%) and for systolic blood pressure response, a similar trend was observed.⁵⁴ Although serum concentrations of irbesartan were not measured in this study, it was suggested that the different therapeutic response in carriers of CYP2C9 variants could be explained with a slower elimination of irbesartan and, thus, greater concentrations of the drug. For candesartan, increased plasma concentrations and decreased clearance of the drug were described in a patient who was carrier of CYP2C9*1/*3 genotype.⁵⁵

Further investigations are needed to answer the question whether genotyping of patients with cardiovascular diseases before treatment with AT₁ receptor antagonists could be beneficial. Nevertheless, from our point of view, currently genotyping procedures in that case are not useful.

Thromboembolic disorders

Patients with thromboembolic disorders like pulmonary embolism or deep vein thrombosis, or those with atrial fibrillation who are at risk of thromboembolic complications need acute or sometimes life-long therapy with anticoagulants. Coumarin anticoagulants, which are vitamin K antagonists, belong to the most frequently prescribed drugs in the world and are characterized by a narrow therapeutic index with both interindividually and intraindividually varying effectiveness. The possible complications in therapy with oral anticoagulants involve severe bleedings or lack of efficacy resulting from, respectively, over- and underanticoagulation. Genetically polymorphic CYP2C9 is one of the factors which could affect safety and efficacy of the treatment with coumarin anticoagulants.

Warfarin

It is estimated that annually more than 1 million patients in the United States are treated with warfarin.⁵⁶ The drug is administered as a racemic mixture of S- and R-warfarin, with S-warfarin being 3–5 times more potent than R-warfarin. S-warfarin is mainly eliminated through 6- or 7-hydroxylation via CYP2C9 so that the activity of this enzyme influences mainly the steady-state plasma concentration of S-warfarin and its antithrombotic activity.⁵⁷ The appropriate therapy with warfarin and other oral anticoagulants of the coumarin type is based on evaluating international normalized ratio (INR), which is normalized prothrombin time.

It could be shown that plasma clearance of S-warfarin, but not the clearance of R-warfarin, depends significantly on CYP2C9 genotype, although nongenetic factors may also contribute to the great interindividual variability in this parameter.⁵⁸ Moreover, for patients with at least one variant allele CYP2C9*2 or CYP2C9*3, a longer induction period to achieve a stable warfarin dosing and an increased risk of INR values above the reference range along with a higher risk of life-threatening bleedings were observed.⁵⁹ Carriers of the CYP2C9 variant alleles were also considerably overrepresented in the group of patients requiring lower maintenance doses of warfarin.⁶⁰ As a result, it was suggested that CYP2C9 genotyping may select a population of patients who are potentially at the risk of complications associated with warfarin therapy.^{59, 60}

Acenocoumarol

Acenocoumarol, the 4'-nitro analog of warfarin, is also administered as a racemic mixture of R- and S-enantiomers and like for warfarin, the metabolism of its S-enantiomer is predominantly mediated by CYP2C9. In contrast to warfarin, the anticoagulation potencies of the R- and S-acenocoumarol are similar, although the mean oral clearance of S-acenocoumarol is essentially greater and its elimination half-life is far shorter than that of the R-enantiomer.⁶¹ Consequently, R-acenocoumarol makes the major contribution to the overall anticoagulation effect.

Results of clinical studies dealing with the role of CYP2C9 polymorphisms in the anticoagulation effect of acenocoumarol are partly contradictory. Whereas some studies showed a considerable effect of CYP2C9 genotype only in patients with at least one CYP2C9*3 allele,^{62, 63} recent data showed that acenocoumarol patients carrying at least one CYP2C9*3 or CYP2C9*2 allele were at the risk of having INR of six or higher and suffering from major bleeding complications.^{64, 65} Moreover, a clear genotype–dose relationship was found in this study so that significant smaller doses of acenocoumarol were suggested for carriers of the CYP2C9 mutant alleles as compared with the wild-type patients.

Phenprocoumon

The influence of CYP2C9 polymorphisms on pharmacokinetics and dynamics of phenprocoumon, another warfarin analog which is favored in a few European countries, was addressed in several clinical studies. Whereas clearance of S-phenprocoumon tended to decrease with the increasing number of CYP2C9*2 and *3 alleles, no influence of both CYP2C9 variants on R-phenprocoumon pharmacokinetic parameters was detected.⁶⁶

Although Visser et al.^{64, 65} could not find significant differences with respect to INR or major bleeding complications between carriers of CYP2C9 variant genotypes and wild-types, results of other studies support the role of CYP2C9 genetic polymorphism in patients treated with phenprocoumon. Hummers-Pradier et al.⁶⁷ found an increased risk of hemorrhage in phenprocoumon patients carrying the CYP2C9*3 allele, but not the CYP2C9*2 allele. However, in another study presenting data of 284 phenprocoumon patients, both mutant alleles CYP2C9*3 and CYP2C9*2 were related to an increased risk of overanticoagulation.⁶⁸

As this review focuses on genetic polymorphisms in DMEs, here we only want to mention briefly the importance of genetic polymorphisms affecting the activity of the vitamin K epoxide reductase complex subunit 1 (VKORC1), which is the target molecule of coumarin anticoagulants, in the antithrombotic therapy. In many clinical trials which have been published recently, it could be shown that VKORC1 genetic polymorphisms also explain a large part of the variability in dose requirements of vitamin K antagonists and therefore, in addition to CYP2C9 polymorphism and demographic factors, play a dominant role in the determination of individual dose.^{69, 70, 71} Moreover, Sconce et al.⁶⁹ proposed a dosing algorithm for individual adjustment of warfarin dose taking into account the CYP2C9 and VKORC1 genotype, age and height, however, such approach should be proved in prospective clinical studies before wide clinical implementation is possible.

Although genetic testing for CYP2C9 and VKORC1 polymorphisms could not replace the role of INR in dose adjustment of coumarin anticoagulants, this procedure certainly may help to identify a group of patients tending toward a longer induction period to achieve a stable dosing and who are potentially at a higher risk of serious bleeding complications.

Ulcer disease and proton pump inhibitors

Proton pump inhibitors (PPIs), such as omeprazole, esomeprazole, lansoprazole, pantoprazole or rabeprazole, are commonly prescribed in a combination with antibiotics for Helicobacter pylori eradication in patients with gastric and duodenal ulcer disease. PPIs undergo extensive presystemic biotransformation in the liver with the involvement of genetically polymorphic CYP2C19. CYP2C19*2 and CYP2C19*3 are the most common nonfunctional alleles which are responsible for the majority of PM phenotypes of CYP2C19.⁷²

Anderson et al.⁷³ observed that in PMs of mephenytoin (a model substrate of CYP2C19) the AUC for omeprazole, lansoprazole and pantoprazole at steady state was fivefold higher compared with EMs indicating that approximately 80% of the dose for all three PPIs is metabolized by CYP2C19. For different PPIs, drug exposures defined using AUC values were 3- to 13-fold higher in PMs and about 2- to 4-times higher in heterozygous EMs as compared to homozygous EMs of CYP2C19.⁷⁴ At the same time, the elevation of intragastric pH as a pharmacodynamic response to PPIs was related directly to the respective AUC and a much higher pH was observed over 24 h following the administration of PPIs in PMs than in EMs.⁷⁴

In a systematic review on pharmacogenetic studies with PPIs, Chong and Ensom⁷⁵ evaluated the effects of CYP2C19 genetic polymorphism on the clinical outcomes, that is, H. pylori eradication rates upon therapy with these drugs. The results of the most studies supported the hypothesis that eradication rates vary with CYP2C19 genotype and in PMs, a significantly better efficacy of PPIs was observed. The authors pointed out that only in a few studies, notably performed with rabeprazole, a similar cure rate irrespective of CYP2C19 genotype was demonstrated. However, rabeprazole undergoes mainly nonenzymatic metabolism and CYP3A4 in addition to CYP2C19 contribute to the enzymatically mediated fraction of its biotransformation.⁷⁶ Nevertheless, in a clinical study determining a cure rate of H. pylori infections upon dual rabeprazole/amoxicillin therapy in relation to CYP2C19 genotype status in Japanese patients, significant differences between homozygous and heterozygous EMs and PMs were noticed (cure rates were 60.6, 91.7 and 93.8%, respectively).⁷⁷

In another study, Furuta et al.⁷⁸ investigated the impact of CYP2C19 genotype on eradication rates of H. pylori upon triple therapy comprising PPI, clarithromycin and amoxicillin. These rates were 72.7, 92.1 and 97.8% in the homozygous extensive, heterozygous extensive and PMs, respectively. The authors confirmed that CYP2C19 genotype seems to be one of the important factors associated with cure rates. Moreover, the same authors could also demonstrate the significance of CYP2C19 genotype for eradication upon dual therapy (amoxicillin as the only antibiotic and high doses of omeprazole) showing cure rates of 100% in PMs.⁷⁹ For that reason, the authors concluded that in Japanese patients homozygous for CYP2C19 defect alleles, the dual therapy might be sufficient. Furuta et al.⁸⁰ also suggested that CYP2C19 genotyping test could be a useful tool for deciding on the optimal treatment regimen with PPIs, including a dual (PPI plus antibiotic) or a triple (PPI plus two antibiotics) therapy.

The role of CYP2C19 polymorphism for eradication of H. pylori was also studied in the Caucasian population. However, in contrast to the Asian population, the prevalence of PM of CYP2C19 in Caucasians is much lower, that is, about 2.8 versus 21.3%, respectively, in Caucasians and Japanese.⁸¹ Schwab et al.⁸² could show significant differences considering the efficacy of lansoprazole-based quadruple therapy between Caucasian patients carrying wild-type alleles, one and two CYP2C19 defect alleles with cure rates of 80.2, 97.8 and 100% in the respective groups. The authors concluded that eradication rates of H. pylori highly depend on CYP2C19 genotype in white patients if the standard doses of lansoprazole are administered within this regimen and carriers of CYP2C19 wild-type allele might benefit from a higher PPIs dosage.

In contrast to these results, the authors of the recently issued meta-analysis evaluating the impact of CYP2C19 polymorphism on H. pylori eradication rates in dual and triple therapies with PPIs concluded that only therapies based on omeprazole undoubtedly depend on CYP2C19 genotype while those with lansoprazole and rabeprazole do not.⁸³ They suggested that genotyping for CYP2C19 could be of greater importance only for the long-term PPI antisecretory therapies in which CYP2C19 impact would be more profound.

In summary, according to the results of numerous clinical studies, CYP2C19 polymorphisms is an important factor affecting the pharmacokinetics of most PPIs, values of intragastric pH and eradication rates of H. pylori. Therefore, in our opinion, genotyping for CYP2C19 polymorphisms could be recommended, first of all in Asian populations characterized by a high prevalence of defect CYP2C19 alleles. The intuitive consequence of this approach would be a higher dosage in the group of EMs and/or an adjusted treatment regimen. The results of prospective controlled clinical trials need to be awaited to see whether patients might benefit from such individually tailored therapy.

Malignant diseases

Most anticancer drugs are characterized by a very narrow therapeutic index and severe consequences of over- or underdosing in the form of, respectively, life-threatening adverse drug reactions or increased risk of treatment failure. Polymorphisms in genes encoding DMEs are considered to be an important factor contributing to individual drug response in patients undergoing antineoplastic chemotherapy.

Thiopurines

Thiopurines, such as 6-mercaptopurine and thioguanine are largely used in the treatment of acute leukemia whereas rheumatoid arthritis is a common field of application for the immunosuppressant azathioprine. These drugs, following their activation to thioguanine nucleotides via the purine salvage pathway, are incorporated into DNA.⁸⁴ At the same time, thiopurine-S-methyltransferase (TPMT) inactivates thiopurine drugs. The individual enzymatic capacity is inherited as an autosomal codominant trait resulting in three distinct phenotypes which show a pronounced ethnic-specific distribution.⁸⁵ Approximately 89% of Caucasians demonstrate a high catalytic TPMT activity while about 11 and 0.3%, respectively, of that population exhibit an intermediate and low activity.⁸⁶ The molecular basis of such interindividual variation is provided by genetic polymorphisms and the alleles *2, *3A and *3C explain about 80–95% of altered enzyme activity.⁸⁷ Impaired TPMT activity is inversely correlated with the generation of thioguanine nucleotides which are responsible for toxicity.^{88, 89} Myelotoxicity is the dose-limiting toxicity of thiopurines, and this adverse event may necessitate discontinuation of therapy and can even lead in fatal outcomes in patients with low TPMT activity if treated with conventional doses.^{90, 91} TPMT genotyping predicts the clinical phenotype with almost complete concordance (at least 95%) and essentially all homozygous carriers of defective alleles are affected by toxic side effects that require discontinuation of therapy.^{90, 92} However, in analysis of 41 patients with Crohn's disease and azathioprine-related hematotoxicity, early onset of intolerance in carriers of mutant TPMT alleles was indeed observed but genetic variants could explain only 27% of all toxic cases.⁹³ Hepatic TPMT activity can reliably be determined by measurement of the catalytic activity of cytosolic TPMT in erythrocytes using established radiochemical or high-performance liquid chromatography (HPLC) methods.^{94, 86} However, several cases of shortcomings of such TPMT phenotyping approaches have been reported. TPMT-deficient patients spuriously exhibited a normal enzyme activity after they had received erythrocyte concentrates of homozygous wild-type donors.^{90, 95} Moreover, the phenotyping results can also be significantly influenced by concomitant therapy with furosemide, sulfasalazine, salicylic acid, intake of certain foodstuff and the presence of uremia.^{96, 97}

For patients treated with thiopurines, an individualized therapy with regard to TPMT genotype has been suggested. Reduction of doses to 5–10% of conventional average doses in carriers of two nonfunctional TPMT alleles has been shown to allow for an efficacious continuation of therapy.^{87, 98, 99} For patients heterozygous for defective TPMT alleles, a full starting dose has been recommended taking into account that a dose reduction to avoid toxicity will be probably required.⁹⁹

In conclusion, present genotyping or phenotyping strategies predict individuals being deficient with respect to TPMT at high accuracy and should routinely precede the onset of therapy with thiopurine-derived drugs in order to minimize life-threatening and cost-intensive myelotoxic adverse events. For 6-mercaptopurine, which is widely used for therapy of acute lymphoblastic leukemia in children, the FDA has implemented respective pharmacogenetic data into the product label, considering the impact of TPMT genotype on severe toxicity as well as the availability of genotypic and phenotypic testing.

5-Fluorouracil

The initial and rate-limiting enzyme in the hepatic metabolism of the chemotherapeutic agent 5-fluorouracil (5-FU) is dihydropyrimidine dehydrogenase (DPD), thus affecting its pharmacokinetics, efficacy and toxicity.^{100, 101, 102} Application of 5-FU is restricted by a narrow therapeutic index and could be complicated by severe toxicity of WHO grade III–IV with symptoms like mucositis and granulocytopenia.¹⁰³ Moreover, severe adverse events have also been observed with capecitabine, which is an orally bioavailable prodrug of 5-FU.¹⁰⁴

Three-to-five percent of Caucasians have been reported to show a reduced enzymatic activity potentially leading to severe 5-FU-related toxicity in cancer patients.¹⁰⁵ However, measuring individual DPD activity in peripheral mononuclear blood cells does not provide a valid phenotyping approach since the correlation with hepatic DPD activity and 5-FU-pharmacokinetics is poor.^{106, 107}

Polymorphisms within the human DPD gene (DPYD) have been associated with DPD deficiency and severe 5-FU-related toxicity in cancer patients. One of the best-described polymorphisms is the so-called exon 14-skipping mutation at the 5'-splice donor site of exon 14 which is present at a prevalence of only 1% in the Caucasian population but has been detected in 24% of patients suffering from WHO grade IV toxicity upon treatment with 5-FU.¹⁰⁸ To identify patients at increased risk for severe 5-FU-induced toxicity, routine screening for the exon 14-skipping mutation before onset of chemotherapy has been recommended.¹⁰⁹ However, the predictive relevance of genotyping for this mutation is still controversially discussed since the genotype–phenotype correlation is apparently incomplete.¹¹⁰

In a study in patients who had suffered from severe toxicity owing to treatment with 5-FU, direct sequencing of all exons revealed possible genetic causes in 8 out of 14 subjects. Six of them were heterozygous carriers of the exon 14-skipping mutation.¹¹¹ Screening for known mutations in a cohort of cancer patients undergoing 5-FU chemotherapy explained a low DPD activity phenotype only in 17% of all cases and the sole carrier of the exon 14-skipping mutation was inconspicuous with regard to enzyme activity.¹⁰⁵ Moreover, the sample sizes of the previous studies are virtually too small to dare a valid estimation of the clinical value of DPYD genotyping in order to prevent 5-FU-related toxicity. Currently, the predictive value of genotyping of DPYD for individualized anticancer therapy needs further elucidation in large prospective studies.

Irinotecan

Recently, much attention has been paid to importance of pharmacogenetic polymorphisms in uridine diphosphate glucuronosyltransferase (UGT) and its role in toxicity and therapeutic response in cancer patients undergoing treatment with the potent antitumor agent irinotecan. SN-38, the active metabolite of irinotecan and topoisomerase I inhibitor, is glucuronidated to its inactive form by UGT1A1, the UGT enzyme which is also responsible for glucuronidation of bilirubin.¹¹² Several variant alleles leading to reduced enzymatic UGT1A1 activity have been identified in the UGT1A1 gene. These polymorphisms become manifest as unconjugated hyperbilirubinemia in the form of Crigler–Najjar or Gilbert's syndromes as well as, in patients treated with irinotecan, they result in reduced SN-38 glucuronidation rates.¹¹³ For UGT1A1 genetic variations, major interethnic differences have been shown; whereas UGT1A1*28 promoter polymorphism (TA repeat in the promoter) is quite common in the Caucasian population, UGT1A1*6 and UGT1A1*27 situated in the coding region of UGT1A1 are found mainly in Asians.¹¹⁴

Impact of UGT1A1 polymorphisms on irinotecan toxicity, which is characterized by severe diarrhea and neutropenia, has been studied in several retrospective as well as prospective studies. It could be shown that the presence of common UGT1A1 mutant alleles, even in heterozygous carriers, significantly changed the disposition of irinotecan causing severe toxicity in patients.^{114, 115, 116} Consecutively, genotyping for UGT1A1 polymorphisms before therapy with irinotecan was recommended for patients of all ethnic groups. If UGT1A1 genotyping is not possible, total bilirubin level was proposed as an easy surrogate parameter for prediction of life-threatening toxicity due to irinotecan,¹¹⁵ however, usefulness of this approach should definitely be confirmed in further clinical trials. Finally, given the cumulative evidence, the FDA has approved a new labeling for irinotecan in favor of UGT1A1*28 genotyping, which reflects the prevalence of the UGT1A1*28 allele in European Americans. A reduced initial dose of irinotecan has been recommended for homozygous carries of this variant allele as they are at increased risk for neutropenia (FDA, http://www.fda.gov).

In summary, importance of individually tailored medicine for cancer patients seems to be of critical importance to develop safe and effective chemotherapy. Even if genetically polymorphic DMEs are not the only factor contributing to the wide interindividual variation in toxicity and efficacy of anticancer drugs, the recent implementation of the pharmacogenetic data to the product labels of 6-mercaptopurine and irinotecan can be assessed as milestones in oncology and pharmacogenetics.¹¹⁷ However, successful implementation of pharmacogenetic tests in cancer patients would depend on thorough analysis of clinical benefits and cost effectiveness of this approach.

Tuberculosis and isoniazid

Tuberculosis is still a global emergency, first of all due to the growing prevalence of drug resistant Mycobacterium tuberculosis strains and the spread of AIDS infection.¹¹⁸ Isoniazid is a pivotal agent in the treatment of tuberculosis in combination with other drugs, or alone as a prophylactic agent. It is metabolized to acetylisoniazid by the hepatic enzyme N-acetyltransferase type 2 (NAT2). The enzyme is target of genetic polymorphisms and carriers of at least one wild-type allele (NAT2*4) or a high-activity variant allele (NAT2*12) demonstrate high NAT2 activity (rapid acetylator, RA), whereas slow acetylators (SA) have two low-activity variants. Subjects with one high-activity NAT2 allele are sometimes classified as intermediate acetylators (IA). Pronounced interethnic differences in the prevalence of the rapid- and slow-acetylation phenotype have been observed with the highest frequencies of RAs in East Asia (about 58–90%) followed by other parts of Asia and Europe (between 32 and 43%) and the lowest frequencies found in Africa.^{119, 120}

Isoniazid was the first NAT2 substrate for which acetylation polymorphism with its well-known bimodal distribution was described following the observation that peripheral neuropathy, a potential side effect of the drug, is subject to interindividual variation depending on patients' acetylation capacity.¹²¹ Tiittinen et al.¹²² could demonstrate that the metabolism of isoniazid varies interindividually, with mean apparent elimination half-lives of 80 min for rapid acetylators and 180 min for slow acetylators. Subsequently, these earlier findings were complemented by genotyping studies showing a linear relationship of isoniazid pharmacokinetic parameters to the number of highly active NAT2 genes.^{123, 124, 125} According to Kinzig-Schippers et al.,¹²⁵ individual isoniazid clearance could be predicted as clearance (l/h)=10+9 number of NAT2*4 alleles.

At the same time, it was observed that occurrence of adverse effects upon isoniazid therapy is dependent on NAT2 activity, too. In SAs, hepatic toxicity, neurotoxic effects and systemic lupus erythematodes seem to appear more frequent and have more severe course than in phenotypic RAs.¹²⁶ These observations have also been supported by later genotyping studies. In tuberculosis patients treated with isoniazid and rifampicin, a significant association between hepatotoxicity and NAT2 genotype was observed so that compared with patients with two highly active NAT2 alleles, the relative risk was 4 for patients with one highly active NAT2 allele and 28 for patients with no highly active NAT2 allele. The authors suggested that NAT2 genotyping before therapy could be useful.¹²⁷ Likewise, Huang et al.¹²⁸ could show in a study in 224 tuberculosis patients that carriers of no highly active NAT2 alleles had a higher risk for hepatotoxicity than those with at least one highly active NAT2 allele, that is, 26 versus 11%. Furthermore, hepatic injury in SAs is more likely to have severe course than in RAs. On the other hand, efficacy of isoniazid therapy seems to be better in SAs and significant differences in the mean early bactericidal activity of isoniazid between homozygous SAs and heterozygous or homozygous RAs could be demonstrated.¹²⁹

Individually tailored therapy with isoniazid, which could warrant optimal therapeutic efficiency and limitation of toxic effects, has not been used in clinical routine so far, although reliable genotyping or phenotyping approaches are available.

Currently, potential benefits of isoniazid dose adjustment according to NAT2 genotype in tuberculosis patients are being assessed in two large European ('IDANAT2') and East Asian studies with participation of the authors of this review in the former. The studies test the hypotheses that by means of adjustment of the isoniazid dose, early treatment failure can be reduced twofold in RAs whereas in SAs hepatotoxicity can be reduced threefold. IDANAT2 has a prospective, randomized, controlled and double-blind design (Figure 1) and should provide a definite answer on dose individualization according to genotype of a DME in this disease of global importance.

Figure 1.

Scheme of a prospective, double-blind, multicenter, parallel group randomized trial to evaluate the possible benefit of isoniazid dose adjustment according to the genotype of N-acetyltransferase type 2 (IDANAT2).

Full figure and legend (32K)

Perspectives

Thousands of manuscripts addressing pharmacogenetic questions in in vitro studies and clinical trials with healthy volunteers or patients have been published in the past decades. Even so, it seems that the way to a broader use of genotyping/phenotyping approaches for DMEs at the patients' bedside and, consequently, implementation of the respective results in the form of personalized pharmacotherapy is quite laborious. There are some possible reasons for this slow progress in clinical pharmacogenetics/pharmacogenomics. Thanks to modern pharmacogenomic technologies, it was found that genetic regulation of DMEs, like other proteins controlling biological processes in living organisms, is actually more complex than initially expected. In reality, gene function is not a constant but it varies depending on environmental factors as well as gene expression could be affected by respective gene products themselves.¹³⁰ For that reason, there is no exact relationship between the genotype and phenotype, that is, the actually measured activity of DMEs, although in many cases the genotype explains most of the interindividual variability. Another essential problem is the lack of prospective clinical studies assessing the merits of genotyping/phenotyping strategies for personalized medicine in large numbers of patients. Similarly, no reliable data on cost effectiveness of such screening procedures exist. A successful implementation of individually tailored medicine would depend not only on further improvement in multigenic testing but also needs to be preceded by numerous prospective studies with clinical endpoints.

In summary

We reviewed the main genetic polymorphisms of DMEs and discussed their potential clinical relevance on pharmacological therapies of common human ailments, with the intention to demonstrate the importance of pharmacogenetic factors for drug toxicity and treatment efficacy in patients. Although interindividual variability in drug response is also caused by many nongenetic factors and the respective genetic factors are probably far more complex than was initially assumed, already today there is a solid place for genotyping for DMEs in some therapies. However, more prospective studies with clinical endpoints are needed before the paradigm of 'personalized medicine' based on DME variants can be established.

Duality of Interest

No conflict of interest exists with any of the authors.

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