Gene Related Metabolism of Drugs

1. Gene Related Metabolism of Drugs Anastasios Maratonitis (2009)

2. There are more than 30 families of drug-metabolizing enzymesin humans, and essentially all have genetic variants, manyof which translate into functional changes in the proteins encoded. The cytochrome P-450 enzymes, a superfamily of microsomal drug-metabolizingenzymes, are the most important of the enzymes that catalyzephase I drug metabolism. One member of this family, cytochromeP-450 2D6 (CYP2D6) will be used as example of gene variation in drug metabolism. More than 75 CYP2D6alleles have been described, subjectswith ultra rapid metabolism have been proven to have multiplecopies of this gene. Such subjects can have an inadequatetherapeutic response to standard doses of the drugs metabolizedby CYP2D6 (the higher the metabolic ratio, the less metabolite isexcreted). The effect of the number of copies ofthe CYP2D6 gene — ranging from 0 to 13 — is well visible on thepharmacokinetics of the antidepressant drug nortriptyline shown in next figure

3. Mean plasma concentrations of nortriptyline after a single 25-mg oral dose are shown in subjects with 0, 1, 2, 3, or 13 functional CYP2D6 genes Although the occurrence of multiple copies of theCYP2D6 gene is relatively infrequent among northern Europeans,in East African populations, the allele frequency can be ashigh as 29 percent

4. The table below lists common drug metabolism gene variants and their frequencies in major ethnic groups. Adapted from Blue Cross Blue Shield Special report

5. The CYP2D6 polymorphism represents an excellent example of boththe potential clinical implications andthe process by which gene research led from the phenotypeto an understanding of molecular mechanisms at the level ofthe genotype. Similar approaches were subsequently applied toother families of drug-metabolizing enzymes. We now know that many other drug-metabolizing enzymesdisplay genetic variation that can influence a person's responseto a drug. The table bellow lists selected examples of those, clinically relevant, variations . In many cases, we also understand the molecular basisof inherited variation in the drug-metabolizing enzymes.

6. (GENE) DRUGS RESPONSES AFFECTED metabolizers CYP2C9 Anticoagulant effect of warfarin CYP2C19 Peptic ulcer response to omeprazole CYP3A4/3A5/3A7 Efficacy of immunosuppressive effects of tacrolimus Dihydropyrimidine Fluorouracil neurotoxicity Dehydrogenase N-acetyltransferase Hypersensitivity to sulfonamides, amonafide toxicity, (NAT2) hydralazine-induced lupus, isoniazid neurotoxicity Glutathione transferases Decreased response in breast cancer, more toxicity (GSTM1, GSTT1, GSTP1) and worse response in acute myelogenous leukemia

7. P-glycoprotein Decreased CD4 response in HIV-infected (ABCB1) patients, decreased digoxin AUC, drug resistance in epilepsy UGT2B7 Morphine plasma levels COMT Enhanced Levodopa drug effect CYP2B6 Ovarian failure due to Cyclophosphamide Thiopurine methyltransferase Thiopurine toxicity and efficacy, (TPMT) risk of second cancers