Genetic Polymorphisms And Type A Adverse Drug Reactions

A gene can be defined as exhibiting genetic polymorphisms if the variant allele exists in the normal population at a frequency of at least 1%. Genetic polymorphisms are a source of variation to drug response in the human body. In relation to type A adverse drug reactions, polymorphisms in both pharmacokinetic and pharmacodynamic parameters can act as predisposing factors (Table 6.4).

To date, most attention has focused on genetically mediated deficiencies of the P450 enzymes, in particular on CYP2D6 (Park, 1986; Pirmohamed and Park, 1996). A drug metabolized by this pathway will show reduced elimination from the body with a consequent increase in half-life. This will lead to dose-dependent toxicity; a typical example is bradycardia with metoprolol in CYP2D6-poor metabolizers (Lennard et al., 1982).

The role of genetic variation in the metabolism of warfarin by CYP2C9 has attracted a great deal of attention recently. Warfarin is the oral anticoagulant of choice in the United Kingdom (Hart et al., 1998). The number of patients attending anticoagulant clinics has doubled in the last 5 years, largely because of its use in atrial fibrillation. The major risk of warfarin treatment is haemorrhage with an incidence of 8-26 per 100 patient-years (Petty et al., 1999); this is related to the intensity of anticoagulation. Minimization of the risk of bleeding depends on accurate clinical prediction of dosage requirements during warfarin therapy. However, this is difficult since there is wide inter-individual variability in the dose necessary to maintain the international normalized ratio (INR) within a target range.

The S-enantiomer of warfarin, which is predominantly responsible for the anticoagulant effect, is metabolized by CYP2C9 (Rettie et al., 1992). Polymorphisms in the CYP2C9 gene result in at least two allelic variants, CYP2C9 *2 (Arg1442Cys) and CYP2C9 *3 (Ile3592Leu) (Fur-uya et al., 1995), both of which have been shown to decrease warfarin clearance in vitro (Haining et al., 1996; Takahashi et al., 1998) and in vivo (Takahashi et al., 1998). Clinically, these variants have been shown to be associated with a reduced warfarin dose requirement, greater difficulty in

Table 6.4. Genetic polymorphisms and dose-dependent adverse drug reactions.

Area affected

Polymorphic gene

Example of drug affected

Adverse reaction

Phase I metabolizing enzyme

Cytochrome P450 2D6 (CYP2D6)

Metoprolol

Bradycardia

Phase II metabolizing enzyme

Thiopurine methyl transferase

6-mercaptopurine

Bone marrow suppression

Drug transporter

P-glycoprotein (MDR1)

Digoxin

Digoxin toxicity

Target enzyme

Acetylcholinesterase

Pyridostigmine

Neurotoxicity

Receptor

Dopamine D3 receptor

Chlorpromazine

Tardive dyskinesia

Ion channel

Delayed rectifier potassium channel (1Kr)

Clarithromycin

Prolonged QT interval and torsades de pointe

Adapted from Pirmohamed and Park (2001a).

Adapted from Pirmohamed and Park (2001a).

initiating warfarin treatment, and an increased risk of bleeding (Aithal et al, 1999). Although the relationship between CYP2C9 genotype and dose requirement has been confirmed in two other studies (Freeman et al., 2000; Taube et al., 2000), one of which was much larger (n = 561) (Taube et al., 2000), the relationship with severe over-anticoagulation and hence bleeding was not.

On the basis of these studies, should all patients starting warfarin be genotyped? This is probably premature since a number of confounding factors need to be studied (Pirmohamed and Park, 2001a). First, the anticoagulant response is partly dependent on R-warfarin, which is metabolized by CYP1A2 and CYP3A4 (Kaminsky and Zhang, 1997). Second, there are a number of pharmaco-dynamic factors, such as vitamin K status and thyroid disease, which alter sensitivity to anticoagulants (Scott, 1989). Third, there are mutations in the clotting factors such as prothrombin that may alter sensitivity to warfarin (Taube et al., 2000). Fourth, there are other methods of dose titration and dose maintenance with warfarin, for example prescribing by computer program (Poller et al., 1998) or home monitoring (Cromheecke et al., 2000), which have been shown to be more effective than conventional prescribing. Finally, the clinical use of warfarin dictates that the genotype of the patient would be required within 24 hours of admission. Thus, before genotyping prior to warfarin treatment can become a routine part of clinical practice, there is a need for a prospective randomized clinical trial, which not only incorporates into its trial design the different methods for monitoring and altering warfarin dosage, but also the confounding factors mentioned above.

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