CYP2D6
- CYP2D6 is responsible for metabolism of:
- Codeine to morphine, via O-demethylation
- Tramadol to its O-methyl metabolite, which has 1000x μ-opioid (MOP) receptor potency
- Allelic variations cause a significant effect in the metabolism of some opioids
- Patients can be classed as:
- Ultra-fast metabolisers - gene duplications cause a larger proportion of drug conversions and side-effects, and increased morphine in breast milk, occurs in 30% East Africans
- Expected metabolisers
- Poor metabolisers - absent function with CYP2D6 *3 / *4 / *5 and *9 alleles, occurs in 7-10% of Caucasians
CYP2C9
- Responsible for the metabolism of S-warfarin
- S-warfarin is a vitamin K reductase (VKOR) inhibitor, with VKOR itself also exhibiting genetic variability
- This necessitates treatment algorithms for warfarin based on ethnicity, gender, weight/height, other drugs used etc.
CYP2C19
- Responsible for the metabolism of the pro-drug clopidogrel to its active form
- CYP2C19 genotypes include:
- *1 (wild type) - normal activity
- *2 and *3 (approx. 30%) - reduced activity and may require alternative antiplatelets
- *17 has increased activity although this doesn't require alternative therapeutic strategies
CYP2C & CYP24A
- Genetic polymorphisms of these renal CYP enzymes can predispose to hypertension
Acetyltransferases
- Hepatic N-acetyltransferases (NAT1 and NAT2) are responsible for acetylation as part of hepatic phase II metabolism, as well as processing of carcinogens
- Paracetamol, isoniazid, hydralazine are amongst drugs metabolised via this pathway
- Patients may have different acetylation status depending on their genotype:
- Fast acetylator status is inherited in an autosomal dominant fashion (40% of population)
- Slow acetylator status is inherited in an autosomal recessive fashion (60% of population)
- Slow acetylators (NAT2*5 allele) represent 50% of the Caucasian population