CYP2D6 has received intense attention since the beginning of the pharmacogenetic era in the 1970s. This is because of its involvement in the metabolism of more than 25% of the marketed drugs, the ...large geographical and inter-ethnic differences in the genetic polymorphism and possible drug-induced toxicity. Many interesting reviews have been published on CYP2D6 and this review aims to reinstate the importance of the genetic polymorphism of CYP2D6 in different populations as well as some clinical implications and important drug interactions.
We have proposed that 4β‐hydroxycholesterol (4β‐OHC) may be used as an endogenous marker of CYP3A activity. The cholesterol metabolite 4β‐OHC is formed by CYP3A4. Treatment of patients with strong ...inducers of CYP3A enzymes, e.g. anti‐epileptic drugs, resulted in 10‐fold increased concentrations of plasma 4β‐OHC, while treatment with CYP3A inhibitors such as ritonavir or itraconazole resulted in decreased plasma concentrations. There was a relationship between the 4β‐OHC concentration and the number of active CYP3A5*1 alleles showing that 4β‐OHC was not only formed by CYP3A4, but also by CYP3A5. The concentration of 4β‐OHC was higher in women than in men, confirming previous studies indicating a gender difference in CYP3A4/5‐activity. The rate of elimination of 4β‐OHC is slow (half‐life 17 days) which results in stable plasma concentrations within individuals, but limits its use to study rapid changes in CYP3A activity. In short‐term studies exogenous markers such as midazolam or quinine may be superior, but in long‐term studies 4β‐OHC is a sensitive marker of CYP3A activity, especially to assess induction but also inhibition. Under conditions where the cholesterol concentration is changing, the ratio of 4β‐OHC : cholesterol may be used as an alternative to 4β‐OHC itself. The use of an endogenous CYP3A marker has obvious advantages and may be of value both during drug development and for monitoring CYP3A activity in patients.
We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations.
ART naïve HIV ...patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done.
Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART.
We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To investigate the CYP1A2 genotype-phenotype relationship and to compare CYP1A2 genetic polymorphisms and enzyme activity in terms of the effect of smoking and oral contraceptive (OC) use in Swedes ...and Koreans.
CYP1A2 enzyme activity was determined in 194 and 150 healthy Swedish and Korean subjects, respectively, on the basis of the 4-h plasma paraxanthine/caffeine (17X/137X) ratio determined using high-performance liquid chromatography. Genotyping for the -3860G>A, -2467delT, -739 T>G, -729 C>T, -163C>A and -3113A>G polymorphisms was performed by PCR-restriction fragment length polymorphism analysis.
The mean 17X/137X ratio was 1.54-fold higher in Swedes than in Koreans (mean difference: 0.16; 95% CI of the mean difference: 0.12, 0.20; p < 0.0001). Smokers had a significantly higher 17X/137X ratio (higher CYP1A2 activity) than non-smokers, while Swedish OC users had a significantly lower 17X/137X ratio than non-users (mean difference: 0.31, 95% CI of the mean difference: 0.23, 0.39; p < 0.0001). No effect of gender differences on enzyme activity was observed. Four known (CYP1A2*1A, *1D, *1F, and *1L) and two novel haplotypes (CYP1A2*1V and CYP1A2*1W) were found. CYP1A2*1K was rare in Swedes and absent in Koreans. No significant genotype-phenotype relationship was observed, with the exception of CYP1A2*1F in Swedish smokers, where it was associated with higher enzyme inducibility (p = 0.02). Koreans displayed a significantly lower mean 17X/137X ratio than Swedes having the same CYP1A2 genotype, smoking habit and OC use.
We found significant differences in CYP1A2 enzyme activity between Swedes and Koreans that could not be explained by environmental factors or the CYP1A2 haplotypes examined, despite differences in allele frequencies. None of the investigated CYP1A2 haplotypes are critical in inducing variations in enzyme activity, with the exception of CYP1A2*1F.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• The only existing study of CYP2C19*17‐associated alterations in drug pharmacokinetics was retrospective and compared probe drug metabolic ratios.
• The ...CYP2C19*17 allele had been associated with a two‐ and fourfold decrease in omeprazole and S/R‐mephenytoin metabolic ratios.
WHAT THIS STUDY ADDS
• This study characterized the single‐dose pharmacokinetics of omeprazole, along with the 5‐hydroxy and sulphone metabolites, in CYP2C19*17/*17 and CYP2C19*1/*1 subjects.
• The observed differences in omeprazole AUC∞ suggest that the CYP2C19*17 allele is an important explanatory factor behind individual cases of therapeutic failure.
AIMS
To investigate the influence of the CYP2C19*17 allele on the pharmacokinetics of omeprazole, a commonly used CYP2C19 probe drug, in healthy volunteers.
METHODS
In a single‐dose pharmacokinetic study, 17 healthy White volunteers genotyped as either CYP2C19*17/*17 or CYP2C19*1/*1 received an oral dose of 40 mg of omeprazole. Plasma was sampled for up to 10 h postdose, followed by quantification of omeprazole, 5‐hydroxy omeprazole and omeprazole sulphone by high‐performance liquid chromatography.
RESULTS
The mean omeprazole AUC∞ of 1973 h nmol l−1 in CYP2C19*17/*17 subjects was 2.1‐fold lower 95% confidence interval (CI) 1.1, 3.3 than in CYP2C19*1/*1 subjects (4151 h nmol l−1, P = 0.04). A similar trend was observed for the sulphone metabolite with the CYP2C19*17/*17 group having a mean AUC∞ of 1083 h nmol l−1, 3.1‐fold lower (95% CI 1.2, 5.5) than the CYP2C19*1/*1 group (3343 h nmol l−1, P = 0.03). A pronounced correlation (r2 = 0.95, P < 0.0001) was seen in the intraindividual omeprazole AUC∞ and omeprazole sulphone AUC∞ values.
CONCLUSIONS
The pharmacokinetics of omeprazole and omeprazole sulphone differ significantly between homozygous CYP2C19*17 and CYP2C19*1 subjects. For clinically important drugs that are metabolized predominantly by CYP2C19, the CYP2C19*17 allele might be associated with subtherapeutic drug exposure.
Objectives
To investigate the influence of coffee consumption on CYP1A2 enzyme activity controlling for the effects of smoking and oral contraceptive (OC) use among Serbs and Swedes and to compare ...CYP1A2 activity between the two populations.
Methods
Data on oral contraceptive use, habitual coffee consumption and smoking habits were obtained from 100 Serbian and 149 Swedish healthy volunteers using a detailed questionnaire. CYP1A2 activity was estimated by plasma paraxanthine/caffeine (17X/137X) ratio analysed by reversed-phase HPLC after oral administration of 100 mg caffeine.
Results
Daily consumption of at least three cups of coffee significantly increased CYP1A2 enzyme activity in both Serbs (
P
= 0.0002) and Swedes (
P
< 0.0001). Among non-smokers and non-OC users, heavy coffee consumption significantly increased CYP1A2 activity in Serbs (mean difference 0.11; 95% CI of the mean difference 0.04, 0.18;
P
= 0.003) and Swedes (mean difference 0.07; 95% CI of the mean difference 0.01, 0.12;
P
= 0.02). Significantly higher 17X/137X ratio was detected in Serbian smokers compared to non-smokers. There was no significant gender difference in CYP1A2 activity in Serbs. Controlling for the effect of smoking, heavy coffee consumption habit and oral contraceptive use, significantly lower 17X/137X ratio was observed in Serbs than in Swedes (
P
= 0.0003).
Conclusions
Habitual heavy coffee consumption increases CYP1A2 activity. Polycyclic aromatic hydrocarbons formed during roasting of coffee beans might partly be responsible for this effect. The reason for the observed lower CYP1A2 activity in Serbs as compared to Swedes remains to be investigated.
Purpose The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and ...age, was investigated in patients with schizophrenia. Methods A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine. Results In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact. Conclusions At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established.
Objectives To compare CYP2C19 enzyme activity between Swedes and Koreans controlling for the effect of CYP2C19 genotype, sex, oral contraceptive use, and smoking habits. Methods CYP2C19 activity was ...determined in 185 healthy Swedish and 150 Korean subjects as the omeprazole/5-hydroxyomeprazole ratio (metabolic ratio; MR) using high-performance liquid chromatography. Genotyping was performed by PCR using Taqman assay. Results As expected, a higher incidence of poor metabolizers (PM) was found in Koreans (14%) compared with Swedes (3.8%) and the frequency of the CYP2C19*17 allele was very low in Koreans (0.3%). Among subjects homozygous for CYP2C19*1, Koreans displayed significantly lower CYP2C19 enzyme activity than Swedes (p < 0.000001). Interestingly, in Koreans a pronounced gender difference was apparent: females (n = 24) had significantly lower MR than males (n = 30; p < 0.0001), but such a gender difference was not seen among Swedes. Swedish OC users had a higher MR than non-users (p < 0.00001), whereas OC was only used by one Korean. No effects of smoking were observed. Conclusions We find specific gender-dependent effects of CYP2C19 activity in Koreans, but not in Swedes. Controlling for the effect of genotype and sex, Koreans display lower CYP2C19 activity than Swedes. The genetic, epigenetic or environmental basis for this difference remains to be identified.
The aim was to compare cytochrome P450 2A6 (CYP2A6) genotype and enzyme activity between Swedes and Koreans, and to investigate the influence of genotype, sex, age, cigarette smoking and oral ...contraceptive (OC) use on enzyme activity. The study involved 190 Swedes and 144 Koreans. Genotyping for CYP2A6*1B, *1 × 2, *4, *5, *7, *8, *9, *10, *18 and *19 alleles was done. Using caffeine as a probe, in vivo CYP2A6 activity was estimated by the 17U/17X urinary ratio. Multiple regression analysis indicated ethnicity (p = 0.0001) and CYP2A6 genotype (p = 0.006), but not sex, age, cigarette smoking or OC use as predictors of CYP2A6 activity. There were significant differences in CYP2A6 genotype distribution and enzyme activity between Swedes and Koreans. Functional CYP2A6 alleles and rapid genotypes were more frequent in Swedes, whereas the defective alleles and slow genotypes were more frequent in Koreans (p ≤ 0.0001). Distribution of log 17U/17X was bimodal in Koreans but unimodal in Swedes with a common antimode at 0.01, classifying 3.16% of Swedes and 18.75% of Koreans as slow metabolizers. CYP2A6 activity was higher in Swedes compared to Koreans (p < 0.0001), even among carriers of rapid genotypes. We report major differences in CYP2A6 enzyme activity between Swedes and Koreans mainly due to CYP2A6 genetic variation but not exclusively.
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