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Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population
Objective
The purpose of the study was to study the distribution of poor and extensive metabolizers of CYP2C19 and CYP2D6 and to genotype for CYP2C8 and CYP2C9 among 312 randomly selected Faroese.
Methods and results
The participants were phenotyped for CYP2D6 with the use of sparteine. The distribution of the sparteine metabolic ratio (sparteine/didehydrosparteines) was bimodal, and 14.5% (n=44; 95% CI: 10.7–18.9%) of the subjects were phenotyped as poor metabolizers. The frequency of poor metabolizers was higher (P=0.0002; χ2 test) among the Faroese than in other European populations (7.4%). Genotype analyses for the CYP2D6*3, *4, *6 and *9 alleles were performed using real-time polymerase chain reaction (PCR) (TaqMan, Foster City, CA, USA), and we found 14.6% (n = 45) (95% CI: 10.8–19.0%) with deficient CYP2D6 genes (*3/*4, *4/*4, *4/*6, *6/*6) in the Faroese population. The subjects were phenotyped for CYP2C19 with the use of mephenytoin and 10 subjects, i.e., 3.2% (95% CI: 1.6–5.9%) were phenotyped as poor metabolizers. Genotype analysis for the CYP2C19*2 and *3 alleles was performed by means of PCR analysis, and 2.9% (n=9) (95% CI: 1.3–5.4%) of the Faroese were found to have a deficient CYP2C19 gene all explained by the CYP2C19*2/*2 genotype. The allele frequencies of the CYP2C9*2 and CYP2C9*3 alleles were 8.8% (95% CI: 6.7–11.4%) and 5.3% (95% CI: 3.7–7.4%), respectively, while the CYP2C8*3 allele frequency was 6.9% (95% CI: 5.0–9.2%). Real-time PCR (TaqMan) was used for both CYP2C9 and CYP2C8 genotype analyses.
Conclusion
The frequency of CYP2D6 poor metabolizers is twofold higher among the Faroese population than other Caucasians, while the frequencies of Faroese subjects with decreased CYP2C19, CYP2C8 and CYP2C9 enzyme activity are the same as seen in other Caucasian populations. A possible consequence might be a higher incidence of side effects among Faroese patients taking pharmaceuticals that are CYP2D6 substrates
Interindividual variation in drug metabolism with focus on polymorphic cytochrome P 450 2C9
Cytochromes P450 (CYP) are enzymes, mainly catalysing the oxidation of
xenobiotics, in order to facilitate their excretion from the body. CYP2C9
is a polymorphic enzyme, which is responsible for the metabolism of about
10 % of all known drugs, e.g sulphonylureas, anticoagulants, angiotensin
II blockers and NSAIDs, which show a considerable interindividual
variation in their metabolic clearance. The primary aim of this PhD
thesis was to investigate possible factors, which could be responsible
for, or contribute to, the variation in CYP2C9 metabolic activity. We
also wanted to further elucidate the impact of CYP2C9 genotypes on the
turnover of both exogenous and endogenous substrates.
In healthy Caucasians a three-fold higher metabolic ratio (MR) of the
CYP2C9 probe drug losartan was found in volunteers genotyped as
CYP2C9*1/*3 compared to CYP2C9*1/*1 subjects (p<0.05), even though there
was considerable variation within each genotype group. The subjects
homozygous for the CYP2C9*3 allele had metabolic ratios that were between
22 and 220 times higher than CYP2C9*1/*1 subjects. No novel allelic
variants of CYP2C9, explaining the low metabolic activity in some of the
CYP2C9*1/*1 subjects, could be identified. A two-fold higher metabolic
ratio of losartan was evident in women taking oral contraceptives (OCs)
compared to women not taking OCs (p< 0.05), showing that CYP2C9-dependent
drug metabolism is reduced during concomitant intake of OC.
When comparing healthy Swedish and Korean subjects, it was discovered
that Swedes had a slower losartan metabolism than Koreans, regardless of
genotype. No difference between female subjects of the two populations,
having the same genotype, was detected. Swedish men, though, had a higher
metabolic ratio (MR=0.83) than Korean men (MR=0.54), p< 0.001, but no
novel polymorphisms could explain this difference.
The intrinsic clearance of the selective COX-2 inhibitor celecoxib was
studied in human liver microsomes of different CYP2C9 genotypes, as well
as in yeast microsomes with recombinantly expressed CYP2C9 variants. The
formation rate of OH-celecoxib was significantly reduced in CYP 2C9*3
samples, compared to samples with two functional alleles. The CYP2C9*2-samples
did not differ from CYP2C9*1 in any of the systems studied. Alcohol
dehydrogenase (ADH1 and ADH2) was identified as being responsible for the
further oxidation of OH-celecoxib, in vitro.
After a single oral dose of 200 mg celecoxib, the exposure was three
times higher in healthy CYP2C9*3/*3 subjects than in CYP2C9*1/*1 and
CYP2C9*1/*3 subjects. After one week of repeated celecoxib
administration, the celecoxib exposure was more than seven times higher
in subjects genotyped as CYP2C9*3/*3, compared to individuals in the
other two genotype groups. The heterozygous CYP2C9*3 carriers were almost
identical to CYP2C9*1/*1 subjects. Subjects genotyped as CYP2C9*3/*3 may
be more likely to experience concentration-dependent side-effects after
long-term treatment with celecoxib.
In human liver microsomes there was a significantly lower formation rate
of epoxyeicosatrienoic acids (EETs) by 34% in samples with the composite
genotype of CYP2C8 *3/*3/CYP2C9*2/*2 compared to CYP2C8 *1/*1/CYP2C9*1/*1.
Inhibition experiments confirmed the involvement of both CYP2C8 and
CYP2C9 in the oxidation of arachidonic acid to vasoactive metabolites.
The results imply that variant alleles of CYP2C8 and CYP2C9 might be
involved in the pathophysiology of cardiovascular diseases.
The ratio between the parent compound and its metabolite. A high MR
reflects a low metabolic activity
Patient and Disease Characteristics for Patients Receiving Multiple Doses.
<p>BSA = body surface area; IL-20 = interleukin 20; PASI = Psoriasis Area and Severity Index score.</p><p>Patient and Disease Characteristics for Patients Receiving Multiple Doses.</p
Study design.
<p>The first dose in the multiple-dose dose-escalation phase was administered after the third dose level of the single-dose dose-escalation phase (0.2 mg/kg) was evaluated by a study safety group; thereafter, the single- and multiple-dose dose-escalation phases were performed in parallel.</p
Summary of Pharmacokinetic Parameters After Dosing With Anti‒IL-20.
<p>AUC = area under the curve; C<sub>max</sub> = maximum concentration; CV = coefficient of variation; IL-20 = interleukin 20; t<sub>½</sub> = half-life.</p><p>Summary of Pharmacokinetic Parameters After Dosing With Anti‒IL-20.</p
Mean PASI total score by visit.
<p>Mean PASI total score by visit following (A) single dosing or (B) multiple dosing in the dose-escalation phase and (C) multiple dosing in the expansion phase. PASI = Psoriasis Area and Severity Index.</p
Patient and Disease Characteristics for Patients Receiving Single Doses.
<p>BSA = body surface area; IL-20 = interleukin 20; PASI = Psoriasis Area and Severity Index score.</p><p>Patient and Disease Characteristics for Patients Receiving Single Doses.</p
Consort flow diagram.
<p>Patient disposition in (A) the single-dose and multiple-dose dose-escalation phases and (B) the multiple-dose expansion phase. Represents the safety analysis set. AE = adverse event.</p