Cytochrome P450 3A4/3A5 Genotyping

Cytochrome P450 3A4 and 3A5 (CYP3A4/3A5) are drug-metabolizing enzymes involved in the metabolism of several clinically important drugs, including the immunosuppressant tacrolimus. The CYP3A4 and CYP3A5 enzymes have a high degree of sequence similarity and metabolize largely the same set of drugs; genotype and metabolic activity for CYP3A4 and CYP3A5 may therefore be considered together when assessing possible effects on drug response. Individuals with some CYP3A4/3A5 alleles may experience a reduced therapeutic response to drugs that are metabolized by CYP3A4/3A5. CYP3A4/3A5 genotype information can be utilized to predict CYP3A4/3A5 metabolic phenotype, which can be used as an aid in determining a therapeutic strategy for drugs that are metabolized by CYP3A4/3A5. For example, the CYP3A5*3 allele confers poor metabolic activity and has a high frequency in most populations, therefore CYP3A5*3/*3 homozygotes (poor metabolizers) predominate. Treatment with tacrolimus for a poor metabolizer typically requires standard dosing, while intermediate or rapid metabolizers typically require higher starting doses.

Variation in the CYP3A4/3A5 genes can result in normal (NM), intermediate (IM) and poor (PM) drug-metabolizing phenotypes. In general, relative to the *1 allele (normal function), the CYP3A4*22 allele has decreased function whilst CYP3A5 *3, *6 and *7 alleles have no function.