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Pharmacogenetics of disease-modifying anti-rheumatic drugs

https://doi.org/10.1016/j.berh.2004.02.006Get rights and content

Abstract

The outcome of treatment with disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients is considerably variable and is also unpredictable. It would be useful clinically if physicians were able to predict responses to DMARDs prior to their administration. One possible cause of differences in efficacy and adverse drug reactions is genetic variation in how individuals metabolize drugs. Based on pharmacogenetics, tailor-made drug therapy, also called personalized drug therapy or individual drug therapy, will be possible with analysis of genetic polymorphism, such as single nucleotide polymorphism (SNP), and analysis of haplotype and diplotype configuration. Several studies of the correlation between the genetic polymorphism of enzymes metabolizing several DMARDs and efficacy or adverse drug reactions have already been reported, suggesting that pharmacogenetics will be applicable to the treatment of RA in the near future.

Section snippets

Methotrexate

Methotrexate (MTX) is one of the most widely used DMARDs for the treatment of RA.1., 2. MTX has proved to be a very effective, fast-acting DMARD with the best efficacy–toxicity ratio. The precise mechanism of action of MTX is still unknown. In approximately 30% of RA patients, toxicity leads to discontinuation of MTX treatment.3 The principal pharmacological effect is thought to be as a folate antagonist. MTX inhibits several enzymes, such as dihydrofolate reductase (DHFR),

Sulfasalazine

Sulfasalazine (SASP) is widely used throughout the world as a second line drug. Use of SASP is sometimes limited because of the occurrence of adverse effects. The frequency of adverse effects with SASP has been reported to be about 20–30% in patients with RA.14

N-acetyltransferase 2 (NAT2) is a key enzyme in the acetylation of several drugs, such as SASP, isoniazid, hydralazine and procainamide. It is well known that rapid and slow acetylator phenotypes exist, determinable by measuring the

D-penicillamine

D-penicillamine (D-PC) has been used in the treatment of RA as an effective DMARD for around 40 years.30 In the process of its metabolism, D-PC undergoes oxidation of its thiol group to form H2O2 in the presence of copper. It has been suggested that the production of H2O2 in vitro inhibits the proliferation of T-lymphocytes and the activity of helper T-cells. D-PC may also act as an antioxidant that scavenges some of the free radicals release by activated neutrophils, leading to reduction of

Azathioprine

Azathioprine (AZA) is widely used to treat malignancies, rheumatic diseases and solid organ transplant rejection. AZA is now used less frequently for treatment of RA because of the changes in the treatment system along with the development of other DMARDs. Thiopurine methyltransferase (TPMT) is one of three major enzymes involved in the metabolism of thiopurine medications, such as AZA and 6-mercaptopurine (6-MP). The presence of mutation in TPMT shunts the drug down the activation pathway to

Cyclophosphamide

Cyclophosphamide (CPA) is an alkylating prodrug clinically used in the treatment of malignancies, auto-immune diseases and in patients undergoing conditioning for renal or bone marrow transplantation. CPA is now rarely used to treat uncomplicated RA. CPA is activated by a 4-hydroxylation reaction catalyzed by the human P450 enzyme, mainly CYP2B6 and -2A6, -2C8, -2C9, -2C18, -2C19 and -3A4.47., 48. CYP3A4 is also the major enzyme responsible for the detoxification of CPA, which involves

Cyclosporin

Cyclosporin A (CsA) is an efficacious second-line agent for patients with active RA who have not responded adequately to MTX.50 CsA is a critical-dose immunosuppressive drug with a narrow theraputic range and wide interindividual variation in its pharmacokinetics. Monitoring of CsA concentration is therefore useful for preventing the adverse effects of CsA, such as hypertension and renal dysfunction. Both cytochrome P450 3A activity in liver, especially CYP3A4 and CYP3A5, and intestinal

Leflunomide

Leflunomide has recently been approved for the treatment of RA in many countries. A771726, the active metabolite of leflunomide, is an immunomodulator which inhibits cell proliferation in activated lymphocytes in patients with active RA. The enzymes involved in leflunomide metabolism and its metabolites have not been clearly determined.56 Several P450 enzymes were tested using marker substrates and human liver microsomes to determine interactions between A771726 and other drugs. Human P450

Hydroxychloroquine

Hydroxychloroquine (HCQ) is an antimalarial drug widely used for the treatment of chronic inflammatory diseases such as RA, systemic lupus erythematosus and photosensitivity diseases, and is generally considered a safe and effective drug. However, 0.5–3.5% of patients taking HCQ exhibit retinal toxicity, the most serious adverse effect of this drug, whereas gastrointestinal toxicity is the most frequent adverse effect of HCQ.

HCQ is metabolized to one major metabolite,

Summary

The outcome of treatment with DMARDs in RA patients is considerably variable and is also unpredictable. It would be useful clinically if physicians were able to predict responses to DMARDs prior to their administration. SNPs are excellent markers of genetic polymorphism. When multiple SNPs exist in a single gene, it is more useful to analyze haplotypes or diplotype configuration (diplotype: a combination of two haplotypes) for determination of genetic polymorphism than to perform SNP analysis.

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