ReviewPharmacogenetics affects dosing, efficacy, and toxicity of cytochrome P450–metabolized drugs
Section snippets
Cytochrome P450 system
Most drugs initially possess lipophilic characteristics that promote the passage of the drug through cell membranes to its site of action. These lipophilic characteristics, however, hinder the elimination of drugs from the body. Consequently, lipophilic drugs must be biotransformed into more hydrophilic metabolites to facilitate elimination and excretion (11). The cytochrome P450 system is a group of enzymes that are responsible for metabolizing many endogenous and exogenous substances (12),
Glipizide
Glipizide is a CYP2C9 substrate (28). In one study (28), toxicity due to glipizide was reported in a subject whose blood glucose was 20 mg/dL approximately 26 hours after glipizide administration (Table 3). Subsequent genotyping revealed that the subject was homozygous for the CYP2C9*3 allele. He was unable to metabolize glipizide efficiently, which resulted in increased exposure to glipizide and prolonged hypoglycemia after a single dose. This case shows how someone with a CYP2C9*3*3 genotype
Cytochrome P450 2C19
The examples described for CYP2C9 illustrate the negative consequences of poor-metabolizer status. However, in some diseases, decreased drug-metabolizing enzyme activity improves drug efficacy.
Codeine
The prodrug codeine is metabolized by CYP2D6 to its active form, morphine 36, 37. Approximately one in 14 whites expresses dysfunctional or inactive enzymes that metabolize codeine to morphine (20). In patients who are CYP2D6 poor metabolizers, codeine is an ineffective analgesic (24). Such patients may be suspected of drug-seeking behavior when they report that codeine is not effective. However, a switch to a different opioid that is not activated by CYP2D6 may provide effective pain relief.
Conclusion
By understanding the clinical implications of pharmacogenetic polymorphisms and their role in affecting individual patient response to drugs, physicians can better explain and avoid drug toxicities and therapeutic failures that occur with standard drug doses, and implement appropriate therapeutic changes. Pharmacogenetics may lead to an appreciation that one dose is not right for all patients, and be used to guide patient-specific medication selection and to individualize dosing regimens.
References (40)
- et al.
Clinical application of pharmacogenetics
Trends Mol Med
(2001) - et al.
Polymorphic human cytochrome P450 enzymesan opportunity for individualized drug treatment
Trends Pharmacol Sci
(1999) - et al.
Pharmacogenomicsa clinician’s primer on emerging technologies for improved patient care
Mayo Clin Proc
(2001) Clinical pharmacogenomicsapplications in pharmaceutical R&D
Drug Discov Today
(2001)- et al.
The genetic polymorphism of debrisoquine/sparteine metabolism-clinical aspects
Pharmacol Ther
(1990) - et al.
Opportunities and strategies for introducing pharmacogenetics into early drug development
Drug Discov Today
(2001) Pharmacogenetics and adverse drug reactions
Lancet
(2000)- et al.
Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications
Lancet
(1999) - et al.
Are poor metabolisers of sparteine/debrisoquine less pain tolerant than extensive metabolisers?
Pain
(1993) - et al.
Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation
Pain
(1998)