Genetic Polymorphism
Genetic polymorphism plays a major role modulating drug interactions with the CYP metabolic enzyme system,and contributes to the classification of an individual as either a “poor metabolizer” or an “extensive metabolizer.” Poor metabolizers probably lack a gene for certain isozymes and cannot metabolize certain drug substrates well while extensive metabolizers have the appropriate gene for the isozyme and metabolize drugs normally. Poor metabolizers may achieve toxic serum drug concentrations when usual doses of certain drugs are prescribed for them, or, if the active drug moiety is a metabolite, they may not achieve the desired pharmacologic effect from the drug. They constitute a minority of the population.
The ethnic background of a patient can influence the likelihood that he or she will be a poor or extensive metabolizer. The incidence of individuals classified as poor metabolizers for the metabolic isozyme CYP2D6 is about 8% for Caucasians, 4% for African-Americans and <1% for Asians. This information is very important for clinicians because individuals with a CYP2D6 deficiency cannot convert the drug codeine to its active metabolite. These individuals will receive little if any analgesic benefit from taking codeine. Also, they will be unable to metabolize many of the psychotropic drugs — especially phenothiazines — and may experience toxicity when taking usual doses of these drugs. The incidence of poor metabolizers varies for other isoenzymes. For CYP2C19, approximately 5% of Caucasians and 20% of Asians and African-Americans are poor metabolizers. The CYP2C9 isozyme greatly exhibits genetic polymorphism and will be lacking in > or =20% of Caucasians and 2% of Asians and African-Americans.
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CYP Nomenclature
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| Based on the current nomenclature established by Nebert et al., in 1987, the CYP enzymes represent a superfamily consisting of enzyme families designated by an Arabic or Roman numeral, (e.g., CYP3 or CYPIII). Subfamilies are designated by a capital letter (e.g., CYP3A or CYPIIIA), according to the similarity of amino acid sequences of the encoded CYP isoenzymes. The individual gene is designated by an Arabic number (e.g., CYP2C9 or CYPIIC9). This means that a CYP2C9 enzyme is closely related to CYP2C19 (same family and subfamily), somewhat related to CYP2D6 (same family), but not closely related to CYP1A2 (different family). Although the enzymes are somewhat related and share some general characteristics, each is unique and performs a distinct role. |
Epidemiologists report that individuals older than 65 years of age have up to three times as many drug interactions as younger patients. This increased rate involves a number of factors, including age-related changes in physiology, receptor sensitivity, metabolic capacity, and the practice of polymedicine in this population. (However, clinical studies report that increasing age as a factor influencing drug interactions may involve other isozymes but has little impact on CYP3A4 catalytic activity.)
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