Cyp2a6

Poor nicotine metabolizers

Nicotine

Possibly Y risk of addiction

N-acetyltransferase 2

Slow and rapid acetylators

Isoniazid Sulfamethazine Procainamide Amonifide Dapson Sufasalazine Paraminosalicylic acid Heterocyclic amines (food mutagens)

Slow: Y clearance and 9 risk of toxicity, including toxic neuritis, lupus erythematosus, bladder cancer

Rapid: Y efficacy, 9 risk of toxicity in some cases (amonifide); colorectal cancer

Thiopurine methyltransferase

Poor TPMT methylators

6-Mercaptopurine

6-Thioguanine

Azathiopurine

Bone marrow toxicity, liver damage

Dihydropyrimadine dehydrogenase

Slow inactivation

5-Fluorouracil

9 Risk of toxicity

Plasma pseudocholinesterase

Slow ester hydrolysis

Succinylcholine

Prolonged apnea

Aldehyde dehydrogenase

Rapid and slow metabolizers

Ethanol

Slow: facial flushing Rapid: protection from liver cirrhosis

Catechol

O-methyltransferase

Poor and rapid methylators

Levodopa Methyldopa

Poor: increased efficacy

Glucose-6-phosphate dehydrogenase

Poor metabolizers

Primaquine

Hemolysis

UGT-glucuronosyltransferase

Poor metabolizers

Irinotecan

Myelosuppression and diarrhea

aCompiIed from Ingleman-Sundberg et al. (1999), Meyer (2000), Evans and Relling (1999), Sadee (2000) and Manicelli et al. (2000) and references therein.

aCompiIed from Ingleman-Sundberg et al. (1999), Meyer (2000), Evans and Relling (1999), Sadee (2000) and Manicelli et al. (2000) and references therein.

functional overdose results in increased risk of dose-dependent ADRs associated with these drugs. These individuals also are likely to experience lack of efficacy with prodrugs that require activation by this enzyme; lack of morphine-related analgesic response to the prodrug codeine is one example. Ultrarapid metabolizers (1%-10%) carry duplicated or multiduplicated active genes; they will metabolize some drugs very rapidly, never achieving a therapeutic plasma drug concentration (and hence expected efficacy) at a standard dose. Alternately, an ultrarapid metabolizer given codeine may experience an ADR usually associated with morphine because of the increased conversion of prodrug to active drug; this often is true of active metabolites, as well.

Two variant alleles of CYP2C9, which result in reduced affinity for P450 oxidoreductase or altered substrate specificity, are associated with increased risk of hemorrhage with standard doses of the anticoagulant warfarin. The clearance of S-warfarin in patients who are homozygous for one of the polymorphisms is reduced by 90% compared with patients who are homozygous for the wild-type allele (Ingleman-Sundberg et al., 1999). Similar reductions in drug clearance related to one of these polymorphisms have been documented with other CYP2C9 substrates such as ibuprofen and naprox-en (non-steroidal anti-inflammatories), phenytoin (anti-epileptic), tolbutamide (hypoglycemic/anti-diabetic) and losartan (angiotensin II receptor antagonist) (Daly, 1995). The high frequency of these polymorphisms (up to 37% of one British population was heterozygous for one mutant CYP2C9 allele) and the severity of the potential ADR (hemorrhage with warfarin treatment) make this an important consideration in the selection and dose of warfarin and other affected drugs.

Patients who are homozygous for the null allele of CYP2C19 (poor metabolizers) are extremely sensitive to the effects of omeprazole (anti-ulcer), diazepam (anti-anxiolytic), propranolol (^-blocker), amitriptyline (tricyclic anti-depressant) and other drugs (Touw, 1997). CYP2C19 also is involved in the oxidation of the anti-malarial prodrug proguanil to cycloguanil, although it is unknown whether the polymorphism relates to its anti-malarial effects. The frequency of this poly morphism (3%-6% in Caucasians and 8%-23% in Asians) defines it as clinically significant.

Polymorphic alleles have been identified for several Phase II (conjugation) enzymes, and many of these are as important in drug metabolism as those associated with the Phase I (oxidation) enzymes discussed above. N-acetyltransferase 2, sulfotransferases, glucuronosyltransferases, catechol O-methyltransferase, dihydropyrimidine dehydrogenase (DPyDH), and thiopurine methyltransferase (TPMT) are among the Phase II enzymes known to have clinically significant effects on drug metabolism (Mancinelli et al., 2000); some of these are summarized in Table 43.2. Polymorphisms of genes coding for these enzymes are particularly relevant in cancer chemotherapy (severe toxicity for homozygotes of null alleles of TPMT with thioguanine and azathioprine treatment and of DPyDH with 5-flourouracil treatment) and the treatment of Parkinson's disease with L-dopa (low methylators have an increased response to the drug).

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