Cyp2b6

Tolbutamide, warfarin, phenytoin, nonsteroidal anti-inflammatories Mephenytoin, omeprazole, hexobarbital, mephobarbital, propranolol, proguanil, phenytoin ß blockers, antidepressants, antipsychotics, codeine, debrisoquine, dextromethorphan, encainide, flecainide, fluoxetine, guanoxan, N-propylajmaline, perhexiline, phenacetin, phenformin, propafenone, sparteine

Macrolides, cyclosporine, tacrolimus, Ca2+ channel blockers, midazolam, terfenadine, lidocaine, dapsone, quinidine, triazolam, etoposide, teniposide, lovastatin, alfentanil, tamoxifen, steroids Fluorouracil

Isoniazid, hydralazine, sulfonamides, amonafide, procainamide, dapsone, caffeine Several anticancer agents

Mercaptopurine, thioguanine, azathioprine

Irinotecan, bilirubin

Natural product anticancer drugs, HIV protease inhibitors, digoxin Morphine Levodopa Cyclophosphamide

Anticoagulant effect of warfarin Peptic ulcer response to omeprazole

Tardive dyskinesia from antipsychotics, narcotic side effects, codeine efficacy, imipramine dose requirement, b blocker effect

Efficacy of immunosuppressive effects of tacrolimus

5-Fluorouracil neurotoxicity

Hypersensitivity to sulfonamides, amonafide toxicity, hydralazine-induced lupus, isoniazid neurotoxicity Decreased response in breast cancer, more toxicity and worse response in acute myelogenous leukemia Thiopurine toxicity and efficacy, risk of second cancers

Irinotecan toxicity

Decreased CD4 response in HIV-infected patients, decreased digoxin AUC, drug resistance in epilepsy Morphine plasma levels Enhanced drug effect Ovarian failure

(Continued)

Table 4-2

Examples of Genetic Polymorphisms Influencing Drug Response (Continued)

Gene Product (Gene)

Drugs

Responses Affected

Targets and receptors

Angiotensin-converting enzyme

(ACE) Thymidylate synthase ß2 Adrenergic receptor (ADBR2)

ßj Adrenergic receptor (ADBR1) 5-Lipoxygenase (ALOX5) Dopamine receptors (D2, D3, D.)

Estrogen receptor a Serotonin transporter (5-HTT)

Serotonin receptor (5-HT2A)

HMG-CoA reductase Modifiers Adducin

Apolipoprotein E

Modifiers, continued

Human leukocyte antigen Cholesteryl ester transfer protein Ion channels (HERG, KvLQT1, Mink, MiRP1) Methylguanine-deoxyribonucleic acid methyltransferase Parkin MTHFR

Prothrombin, factor V Stromelysin-j Vitamin D receptor

ACE inhibitors (e.g., enalapril) Methotrexate b2 Antagonists (e.g., albuterol, terbutaline)

bj Antagonists

Leukotriene receptor antagonists

Antipsychotics (e.g., haloperidol, clozapine, thioridazine, nemonapride)

Estrogen hormone replacement therapy Antidepressants (e.g., clomipramine, fluoxetine, paroxetine, fluvoxamine) Antipsychotics

Pravastatin

Diuretics

Statins (e.g., simvastatin), tacrine Abacavir

Statins (e.g., pravastatin)

Erythromycin, cisapride, clarithromycin, quinidine

Carmustine

Levodopa Methotrexate Oral contraceptives Statins (e.g., pravastatin) Estrogen

Renoprotective effects, hypotension, left ventricular mass reduction, cough Leukemia response, colorectal cancer response Bronchodilation, susceptibility to agonist-induced desensitization, cardiovascular effects (e.g., increased heart rate, cardiac index, peripheral vasodilation) Response to ß1 antagonists Asthma response

Antipsychotic response (D2, D3, D4), antipsychotic-induced tardive dyskinesia (D3) and acute akathisia (D3), hyperprolactinemia in females (D2) High-density lipoprotein cholesterol Clozapine effects, 5-HT neurotransmission, antidepressant response

Clozapine antipsychotic response, tardive dyskinesia, paroxetine antidepression response, drug discrimination Reduction in serum cholesterol

Myocardial infarction or strokes

Lipid-lowering; clinical improvement in Alzheimer's

Hypersensitivity reactions Slowing atherosclerosis progression

Increased risk of drug-induced torsades de pointes, increased QT interval Response of glioma to carmustine

Parkinson's disease response Gastrointestinal toxicity Venous thrombosis risk

Reduction in cardiovascular events and in repeat angioplasty Bone mineral density

FIGURE 4-6 Pharmacodynamics and pharmacogenetics. The proportion of patients requiring a dosage decrease for the antidepressant drug paroxetine was greater (p = 0.001) in the approximately one-third of patients who have the C/C genotype for the serotonin 2A receptor (5HT2A) compared to the two-thirds of patients who have either the T/C or T/T genotype at position 102. The major reason for dosage decreases in paroxetine was the occurrence of adverse drug effects.

Days

FIGURE 4-6 Pharmacodynamics and pharmacogenetics. The proportion of patients requiring a dosage decrease for the antidepressant drug paroxetine was greater (p = 0.001) in the approximately one-third of patients who have the C/C genotype for the serotonin 2A receptor (5HT2A) compared to the two-thirds of patients who have either the T/C or T/T genotype at position 102. The major reason for dosage decreases in paroxetine was the occurrence of adverse drug effects.

drug pharmacokinetics but apparently modulates pharmacodynamics by predisposing to GI toxicity of the antifolate drug methotrexate in transplant recipients. Following prophylactic treatment with methotrexate for graft-versus-host disease, mucositis was three times more common in patients homozygous for the 677T allele than in those homozygous for the 677C allele.

Many polymorphisms in drug targets predict responsiveness to drugs (Table 4-2). Serotonin receptor polymorphisms predict not only the responsiveness to antidepressants (Figure 4-6), but also the overall risk of depression. b adrenergic receptor polymorphisms have been linked to asthma responsiveness after b agonist therapy, renal function following angiotensin-converting enzyme (ACE) inhibitors, and heart rate following b-blockers. Polymorphisms in 3-hydroxy-3-methylglutaryl coenzyme A reductase have been linked to the degree of lipid lowering following statins, which are inhibitors of this enzyme (see Chapter 35), and to the degree of elevation of high-density lipoproteins among women on estrogen replacement therapy (Figure 4-7).

Hormone-replacement^ therapy/

P=0.004

Hormone-replacement therapy.

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