Chapter 005. Principles of Clinical
Pharmacology
(Part 10)

Multiple Variants Modulating Drug Effects
As this discussion makes clear, for each drug with a defined mechanism of
action and disposition pathways, a set of "candidate genes," in which
polymorphisms may mediate variable clinical responses, can be identified. Indeed,
polymorphisms in multiple genes have been associated with variability in the
effect of a single drug. CYP2C9 loss-of-function variants are associated with a
requirement for lower maintenance doses of the vitamin K antagonist
anticoagulant warfarin. In rarer (<2%) individuals homozygous for these variant
alleles, maintenance warfarin dosages may be difficult to establish, and the risk of
bleeding complications appears increased. In addition to CYP2C9, variants in the
promoter region of VKORC1, encoding a vitamin K epoxide reductase, predict
warfarin dosages; these promoter variants are in tight linkage disequilibrium , i.e.
genotyping at one polymorphic site within this haplotype block provides reliable
information on the identity of genotypes at other linked sites (Chap. 62). Thus,
variability in response to warfarin can be linked to both coding region
polymorphisms in CYP2C9 and promoter haplotypes in the warfarin target
VKORC1.
As genotyping technologies improve and data sets of patients with well-
documented drug responses are accumulated, it is becoming possible to interrogate
hundreds of polymorphisms in dozens of candidate genes. This approach has been
applied to implicate linked noncoding polymorphisms in the HMG-CoA reductase
gene as predicting efficacy of HMG-CoA reductase inhibitors, and in variants in
the gene-encoding corticotrophin-releasing hormone receptor 1 as predicting
efficacy of inhaled steroids in asthma.
Technologies are now evolving to interrogate hundreds of thousands of
SNPs across the genome, or to rapidly resequence each patient's genome. These
approaches, which have been applied to identify new genes modulating disease

drops. Lists of interactions are available from a number of electronic sources.
While it is unrealistic to expect the practicing physician to memorize these, certain
drugs consistently run the risk of generating interactions, often by inhibiting or
inducing specific drug elimination pathways. Examples are presented below and in
Table 5-2. Accordingly, when these drugs are started or stopped, prescribers must
be especially alert to the possibility of interactions.
Table 5-
2 Drugs with a High Risk of Generating Pharmacokinetic
Interactions

Drug Mechanism Examples
Antacids
Bile acid
Reduced
absorption
Antacids/tetracyclines
Cholestryamine/digoxin
sequestrants
Proton pump
inhibitors
H
2
-receptor
blockers
Altered gastric
pH
Ketoconazole absorption
decreased
Rifampin
Carbamazepine

itraconazole
Erythromycin,
clarithromycin
Calcium channel
blockers
Ritonavir
Inhibitor of
CYP3A
Increased concentration and
toxicity of
some HMG-
CoA reductase
inhibitors
cyclosporine
cisapride, terfenadine (now
withdrawn)
Increased concentration and
effects of
indinavir (with ritonavir)
Decreased clearance and
dose requirement for cyclosporine
(with calcium channel blockers)
Allopurinol Xanthine
oxidase inhibitor
Azathioprine and 6-
mercaptopurine toxicity
Amiodarone
Inhibitor of
many CYPs and of P-
glycoprotein

lar
transport
Salicylates increased risk of
methotrexate toxicity