105CYP2C9 Two inherited SNPs termed CYP2C92 (Arg144Cys) and CYP2C93
(Ile359Leu) are known to affect catalytic function. About 35 % of the Caucasian
population carries at least one 2 or 3 allele. CYP2C9 genotyping may be considered
along with the use of nonsteroidal antiinfl ammatory drugs, oral hypoglycemics, vita-
min K antagonistic oral anticoagulants, and phenytoin. However, before instituting
the routine clinical use of genotyping, the benefi ts of genotype-based therapeutic rec-
ommendations need to be confi rmed by randomized controlled clinical trials.
CYP2C19 This is the gene encoding S-mephenytoin hydroxylase and its muta-
tions lead to poor metabolism of the following drugs: amitriptyline, citalopram,
clomipramine, diazepam, imipramine, mephenytoin, omeprazole, and propranolol.
CYP3A This subfamily comprises 3A3, 3A4, and 3A5 isoenzymes in the humans.
Pharmaceutical substrates of this enzyme are: acetaminophen, alprazolam, carbam-
azepine, cyclosporine, diltiazem, erythromycin, lidocaine, lovastatin, nifedipine,
tamoxifen, terfenadine, verapamil and vinblastine. Differences in the expression of
the CYP3A family contribute to variability in the absorption and clearance of drugs
as diverse as calcium channel blockers and HIV protease inhibitors.
Hepatic expression of CYP3A4 varies more than 50-fold among individuals.
Polymorphisms in the CYP3A4 gene may explain the person-to-person variations
seen in the intensity and duration of drug action as well as in the occurrence of side
effects. Understanding the genetic basis of differences in CYP3A4 function will
enable the determination of proper drug dosage for individual patients to achieve an
optimal therapeutic response with minimal side effects.
Only individuals with the full-length CYP3A5 allele (CYP3A5*1) express large
amounts of CYP3A5, whereas those with a truncated CYP3A5 express little or no
CYP3A5. Because polymorphic CYP3A5 is one factor contributing to individual
variation in CYP3A-mediated metabolism of drugs, simple DNA-based tests can
now be used to determine how individual differences in CYP3A5 contribute to the
overall metabolic fate of these CYP3A substrates, to their pharmacodynamic vari-
ability and to disease risk. Prospective patients would fi rst be CYP3A5 genotyped,
followed by targeted drug therapy i.e. tailoring the drug concentration to optimize
systemic concentrations of drug and drug response. This is likely to be most rele-
vant for drugs with narrow therapeutic indices primarily metabolized by CYP3As,
including many anticancer and anti-transplant rejection drugs. This strategy will
enable identifi cation of those patients who are at risk associated with metabolizing
the CYP3A5 substrate faster or slower so that the issue of CYP3A5-dependent vari-
ability in pharmacokinetics can be effectively addressed.
P450 CYP 2D6 Inhibition by Selective Serotonin Reuptake Inhibitors
Most reports of metabolic enzyme inhibition by selective serotonin reuptake inhibi-
tors (SSRIs) have focused on changes in concentration of the affected drug.
For example, studies have addressed elevated desipramine concentrations with