Biomedical Engineering Reference
In-Depth Information
CYP2D6
UMs. In 2009, Lotsch and colleagues conducted a study in 57 healthy
Caucasians to determine if morphine formation from codeine could be predicted
prior to codeine administration by using
CYP2D6
genotype- and phenotype-based
prediction systems [
34
]. Most subjects (87.5 %) with low morphine production
from codeine were correctly identified. However, satisfactory prediction (87.5 %) of
high morphine formation was only achieved when combining genotype with pheno-
typing. There have been multiple case reports of life-threatening adverse events or
fatalities in
CYP2D6
UMs [
36-
40
]. The data from these pharmacogenetic studies
suggest that implementation of pharmacogenetic testing for
CYP2D6
prior to
codeine therapy could improve efficacy and reduce the incidence of drug toxicity if
done in combination with therapeutic drug monitoring of morphine production.
2.3.2
Other Genetic and Nongenetic Factors
CYP2D6 is not the only polymorphic gene involved in the codeine and morphine
metabolic pathway. Approximately 70 % of morphine is glucuronidated to mor-
phine-3- and morphine-6-glucuronide, primarily by UGT2B7. The evidence con-
cerning the influence of UGT2B7 polymorphism on codeine and morphine
metabolism is conflicting and inconclusive. The most well studied SNP in UGT2B7
(UGT2B7*2) did not affect morphine metabolism in vitro [
41,
42
] . Other studies
have identified additional variants that have an impact on morphine metabolism;
however, these studies have not been reproduced in separate cohorts. It is possible
that recently identified variants that alter mRNA splicing of UGT2B7 could
significantly impact the codeine and morphine pathway [
43
] .
Codeine is metabolized to norcodeine by CYP3A4. CYP3A4 is responsible for
the metabolism of approximately 50-60 % of pharmaceuticals used today and is
also important for the metabolism of steroid hormones. There are several known
genetic variants in CYP3A4, but none of them have been shown to cause a pheno-
typic change in drug metabolism. However, coadministration of drugs that are
CYP3A4 substrates, inducers or inhibitors can affect flux through the codeine path-
way. In one case report of a life-threatening opioid intoxication, the authors attrib-
uted the observed toxicity to not only CYP2D6 ultrarapid metabolism but also
inhibition of CYP3A4 activity by other medications [
14
]. Further studies in a larger
study sample are required to determine the effects of coadministration of drugs that
act on CYP3A4 for the metabolism of codeine.
The efflux transporter P-glycoprotein (P-gp), encoded by the ATP-binding cas-
sette BI (ABCB1)/multiple drug resistance 1 (MDR1) gene, is responsible for the
transport of many opioids, including morphine-3-glucuronide and morphine-6-
glucuronide across the blood-brain barrier. Several studies suggest that the
ABCB1:3435C>T variant may influence morphine efflux from the blood-brain
barrier and result in variable analgesic response [
44
]. Also, the same studies have
shown that a polymorphism (OPRM1 118A>G) in the m-opioid receptor, encoded
by the opioid receptor m 1 (OPRM1) gene, is associated with opioid analgesia
