The effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of glipizide in Chinese subjects

Objective  

To study the effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of glipizide.     

Influence of CYP2C9 gene polymorphisms on response to glibenclamide in type 2 diabetes mellitus patients

Purpose  

The antidiabetic drug glibenclamide is metabolized by the enzyme cytochrome P450 2C9 (CYP2C9) encoded by the polymorphic gene CYP2C9. Previous studies involving healthy volunteers have shown a significant influence of variant CYP2C9 genotypes on glibenclamide metabolism. The aim of this study was to investigate the influence of genetic polymorphisms of CYP2C9 on the response to glibenclamide and on glibenclamide plasma levels in type 2 diabetes mellitus patients.     

Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients

AIM

To investigate the impact of genetic polymorphisms in CYP2D6, CYP3A5, CYP2C9 and CYP2C19 on the pharmacokinetics of tamoxifen and its metabolites in Asian breast cancer patients.

METHODS

A total of 165 Asian breast cancer patients receiving 20 mg tamoxifen daily and 228 healthy Asian subjects (Chinese, Malay and Indian; n = 76 each) were recruited. The steady-state plasma concentrations of tamoxifen and its metabolites were quantified using high-performance liquid chromatography. The CYP2D6 polymorphisms were genotyped using the INFINITI™ CYP450 2D6I assay, while the polymorphisms in CYP3A5, CYP2C9 and CYP2C19 were determined via direct sequencing.

RESULTS

The polymorphisms, CYP2D6*5 and *10, were significantly associated with lower endoxifen and higher N-desmethyltamoxifen (NDM) concentrations. Patients who were *1/*1 carriers exhibited 2.4- to 2.6-fold higher endoxifen concentrations and 1.9- to 2.1-fold lower NDM concentrations than either *10/*10 or *5/*10 carriers (P < 0.001). Similarly, the endoxifen concentrations were found to be 1.8- to 2.6-times higher in *1/*5 or *1/*10 carriers compared with *10/*10 and *5/*10 carriers (P≤ 0.001). Similar relationships were observed between the CYP2D6 polymorphisms and metabolic ratios of tamoxifen and its metabolites. No significant associations were observed with regards to the polymorphisms in CYP3A5, CYP2C9 and CYP2C19.

CONCLUSIONS

The present study in Asian breast cancer patients showed that CYP2D6*5/*10 and *10/*10 genotypes are associated with significantly lower concentrations of the active metabolite of tamoxifen, endoxifen. Identifying such patients before the start of treatment may be useful in optimizing therapy with tamoxifen. The role of CYP3A5, CYP2C9 and CYP2C19 seem to be minor.     

Linkage disequilibrium between the CYP2C19*17 allele and wildtype CYP2C8 and CYP2C9 alleles: identification of CYP2C haplotypes in healthy Nordic populations

Purpose

To determine the distribution of clinically important CYP2C genotypes and allele frequencies in healthy Nordic populations with special focus on linkage disequilibrium.

Methods

A total of 896 healthy subjects from three Nordic populations (Danish, Faroese, and Norwegian) were genotyped for five frequent and clinically important CYP2C allelic variants: the defective CYP2C8*3, CYP2C9*2, CYP2C9*3, and CYP2C19*2 alleles, and the CYP2C19*17 allele that causes rapid drug metabolism. Linkage disequilibrium was evaluated and CYP2C haplotypes were inferred in the entire population.

Results

Ten CYP2C haplotypes were inferred, the most frequent of which (49%) was the CYP2C wildtype haplotype carrying CYP2C8*1, CYP2C9*1, and CYP2C19*1. The second most frequent haplotype (19%) is composed of CYP2C19*17, CYP2C8*1, and CYP2C9*1. This predicted haplotype accounts for 99.7% of the CYP2C19*17 alleles found in the 896 subjects.

Conclusion

CYP2C19*17 is a frequent genetic variant in Nordic populations that exists in strong linkage disequilibrium with wildtype CYP2C8*1 and CYP2C9*1 alleles, which effectively makes it a determinant for a haplotype exhibiting an efficient CYP2C substrate metabolism.     

Linkage between the distribution of mutations in the CYP2C18 and CYP2C19 genes in the Japanese and Caucasian

1. Two different types of genetic polymorphisms in each of CYP2C18 and CYP2C19 genes were examined and compared with respect to their frequencies in distribution in liver DNA of 39 Japanese and 45 Caucasians. 2. Individuals who were classified into CYP2C19m1 (as detected with SmaI digestion) in exon 5 of CYP2C19 gene were found to display a CYP2C18m1 polymorphism (as detected with DdeI digestion) in the 5-flanking region of CYP2C18 gene in Japanese and Caucasian populations. The Japanese subjects who were classified into CYP2C19m2 (as detected with BamHI digestion) in exon 4 of CYP2C19 gene were found to have a CYP2C18m2 genetic polymorphism (as detected with Tsp509I digestion) in exon 2 of CYP2C18 gene. None of the Caucasians had the CYP2C18m2 nor CYP2C19m2 alleles. 3. Frequencies in two types (C416T in exon 3, A1061C in exon 7) of CYP2C9 genetic polymorphism were found to be independent to those of CYP2C18 and CYP2C19 genetic polymorphisms in these samples. 4. Thus, the results suggest that the CYP2C18 gene is localized very closely to the CYP2C19 gene on the same human chromosome.     

Lack of association between genetic polymorphisms of CYP3A4, CYP2C9 and CYP2C19 and antituberculosis drug‐induced liver injury in a community‐based Chinese population

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Mild hypoglycaemic attacks induced by sulphonylureas related to <Emphasis Type="Italic">CYP2C9</Emphasis>, <Emphasis Type="Italic">CYP2C19</Emphasis> and <Emphasis Type="Italic">CYP2C8</Emphasis> polymorphisms in routine clinical setting

Aim  

To evaluate the impact of polymorphisms in the cytochrome P450 (CYP) 2C9, 2C19 and 2C8 genes on the risk of mild hypoglycaemic attacks in patients treated with sulphonylureas.     

Responsiveness to low-dose warfarin associated with genetic variants of VKORC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population

Purpose

The aim of this study was to assess the pharmacokinetics and pharmacodynamics of warfarin associated with genetic polymorphisms in VKORC1, CYP2C9, CYP2C19, and CYP4F2 in Indonesian patients treated with low-dose warfarin.

Methods

Genotyping of VKORC1, CYP2C9, CYP2C19, and CYP4F2 was carried out in 103 patients treated with a daily dose of 1–2 mg warfarin, 89 of whom were treated with a fixed daily dose of warfarin (1 mg). The plasma concentrations of S- and R-warfarin and S- and R-7-hydroxywarfarin were used as pharmacokinetic indices, while prothrombin time expressed as the international normalized ratio (PT-INR) was used as a pharmacodynamic index.

Results

In patients treated with a fixed daily dose of warfarin (1 mg), a higher PT-INR was associated with VKORC1-1639 AA [median 1.35; interquartile range (IQR)?1.21–1.50] than with the GA (1.18; IQR?1.12–1.32; p?<?0.01) and GG (1.02; IQR?=?1.02–1.06; p?<?0.01) polymorphisms, and with CYP2C9*1/*3 (1.63; IQR?1.45–1.85) compared to *1/*1 (1.23; IQR??1.13–1.43; p?<?0.05). The S-warfarin concentration was significantly higher in patients with CYP2C9*1/*3 than in those with *1/*1 (p?<?0.05). With low-dose warfarin administration, there was no significant difference in the concentrations of warfarin metabolites among any of the genotype variants. The genotype variations of CYP2C19 and CYP4F2 were not significantly associated with the PT-INR.

Conclusion

For low-dose warfarin treatment, the VKORC1-1639 G?>?A and CYP2C9 genotype variations affected the pharmacokinetics and pharmacodynamics of warfarin, while we could not find significant effects of CYP4F2 or CYP2C19 genotype variations on warfarin (metabolite) concentrations or PT-INR.     

Population pharmacokinetic analysis of glimepiride with <Emphasis Type="Italic">CYP2C9</Emphasis> genetic polymorphism in healthy Korean subjects

Purpose  

The purpose of this study was to develop a population pharmacokinetic (PPK) model of glimepiride and to investigate the influence of genetic polymorphisms in CYP2C9 on the PPK of glimepiride in healthy Korean subjects.     

Genetic Polymorphism of Drug Metabolizing Enzymes: New Mutations in CYP2D6 and CYP2A6 Genes in Japanese

Genetic polymorphism of drug metabolizing enzymes, particularly cytochrome P450 (CYP), is an important cause of adverse drug reactions. Multiple gene mutations in CYP have been shown to be phenotype. The occurrence of genetic polymorphism has been seen in genes for CYP1A1, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A5. This review discusses the molecular mechanism of two genetic polymorphisms, debrisoquine/sparteine (CYP2D6) coumarin (CYP2A6) polymorphisms. In addition, elucidation of gene mutations of CYP2D6 and CYP2A6 in Japanese will be discussed.     

Combination of CYP2C19 genotype with non-genetic factors evoking phenoconversion improves phenotype prediction

Background

CYP2C19 is an important drug-metabolizing enzyme, responsible for metabolism of approximately 10% of the drugs on the market. Large inter-individual differences exist in metabolic activities, which are primarily attributed to genetic polymorphism of CYP2C19 gene. Conflicting results have been published about the role of CYP2C19 polymorphisms in metabolism of CYP2C19 substrates and clinical outcomes; thus, we aimed to investigate CYP2C19 genotype-phenotype associations, and we sought to elicit potential causes of discrepancies in the genotype-based prediction by incorporating the liver donors’ demographic data, drug administration events and pathological conditions.

Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1

AIMS

To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects.

METHODS

Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol.

RESULTS

A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h⁻¹. The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h⁻¹. Absorption rate constant was estimated at 0.24 h⁻¹ and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed.

CONCLUSIONS

The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol.     

CYP2D6 and CYP2C19 genotypes in an elderly Swedish population

Objective: Eighty-three healthy elderly Swedish subjects (age 87 ± 4 years, mean ± SD, range 80–98 years) were genotyped with respect to the two genetic polymorphisms of oxidative drug metabolism, CYP2D6 and CYP2C19, using allele-specific polymerase chain reaction (PCR). A control population consisted of 248 younger unrelated healthy volunteers (age 31 ± 9 years, range 19–63 years) for CYP2D6, and 162 (age 30 ± 8 years, range 19–55 years) for CYP2C19. Results: No significant differences were found between the control groups and the elderly subjects with respect to the frequencies of the defect alleles CYP2D6*3, CYP2D6*4, CYP2C19*2 and CYP2C19*3. Neither were there any differences in the genotype frequencies, or the predicted phenotype frequencies. The study indicates that the CYP2D6 and CYP2C19 genotypes play no major role in the probability of reaching high age. Conclusion: No genetically determined differences in the pharmacokinetics of drugs metabolized by these two polymorphic enzymes are to be expected in the oldest age groups compared with younger adults. Received: 10 March 1998 / Accepted: 1 May 1998     

Genetic polymorphism of CYP2C9 and CYP2C19 in a Bolivian population: an investigative and comparative study

Objective Several reports of CYP2C genetic polymorphism demonstrate its potential clinical role in determining both inter-individual and inter-ethnic differences in drug efficacy. We estimated the distribution of CYP2C9 and CYP2C19 common variants in the Bolivian population (a South American population), and compared these data with those from Asian, African, Caucasian and Oceanian populations.Methods Genomic DNA was obtained from 778 unrelated healthy volunteers from Bolivia. The genotypic status of CYP2C9 and CYP2C19 was determined by means of polymerase chain reaction–restriction fragment length polymorphism.Results Allelic and genotypic frequencies of CYP2C9 and CYP2C19 were determined for the Bolivian population, and comparison of the data with other ethnic groups revealed a lower CYP2C9*2 frequency (4.8%) than in Caucasians, but a higher frequency than in Asians; frequencies of CYP2C9*3 (3.0%) and CYP2C9 (0.4%) poor metabolizers (PMs) were similar to those seen in Asian populations. Frequencies of CYP2C19*2 (7.8%), CYP2C19*3 (0.1%), and CYP2C19 PMs (1.0%) in the Bolivian population were for the most part lower than in Caucasian, Asian, Oceanian and African populations.Conclusion This is the first study to investigate a South American population for genetic polymorphism in the CYP2C subfamily. The Bolivian population differs from most other ethnic groups in the incidence of CYP2C9 and CYP2C19 common variants that might be influenced by its admixture characteristics.     

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; ² 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.     

<Emphasis Type="Italic">CYP2C9*3</Emphasis> and <Emphasis Type="Italic">*13</Emphasis> alleles significantly affect the pharmacokinetics of irbesartan in healthy Korean subjects

Purpose  

To evaluate the effects of two major polymorphisms of CYP2C9, CYP2C9*3 and CYP2C9*13, on the pharmacokinetics of irbesartan in healthy Korean volunteers.     

VKORC1-1639G>A, CYP2C9, EPHX1691A>G genotype, body weight, and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest China

Objective  

To investigate the contribution of genetic polymorphisms of vitamin K epoxide reductase complex subunit 1 gene VKORC1-1639G>A, cytochrome P450 2C9 gene (CYP2C9), EPHXI, and clinical factors to warfarin sensitivity in southwest Chinese Han patients with mechanical heart valve prostheses.     

Pharmacogenomics of CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and MDR1 in Vietnam

Aim  The aim of this study was to obtain pharmacogenetic data in a Vietnamese population on genes coding for proteins involved in the elimination of drugs currently used for the treatment of malaria and human immunodeficiency virus/acquired immunodeficiency syndrome. Method  The main polymorphisms on the cytochrome P450 (CYP) genes, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4 and CYP3A5, and the multi-drug resistance 1 gene (MDR1) were genotyped in 78 healthy Vietnamese subjects. Pharmacokinetic metrics were available for CYP2A6 (coumarin), CYP2C19 (mephenytoin), CYP2D6 (metoprolol) and CYP3As (midazolam), allowing correlations with the determined genotype. Results  In the CYP2 family, we detected alleles CYP2A6*4 (12%) and *5 (15%); CYP2B6*4 (8%), *6 (27%); CYP2C19*2 (31%) and *3 (6%); CYP2D6*4, *5, *10 (1, 8 and 44%, respectively). In the CYP3A family, CYP3A4*1B was detected at a low frequency (2%), whereas CYP3A5 *3 was detected at a frequency of 67%. The MDR1 3435T allele was present with a prevalence of 40%. Allele proportions in our cohort were compared with those reported for other Asian populations. CYP2C19 genotypes were associated to the S-4′-OH-mephenytoin/S-mephenytoin ratio quantified in plasma 4 h after intake of 100 mg mephenytoin. While CYP2D6 genotypes were partially reflected by the α-OH-metroprolol/metoprolol ratio in plasma 4 h after dosing, no correlation existed between midazolam plasma concentrations 4 h post-dose and CYP3A genotypes. Conclusions  The Vietnamese subjects of our study cohort presented allele prevalences in drug-metabolising enzymes that were generally comparable with those reported in other Asian populations. Deviations were found for CYP2A6*4 compared to a Chinese population (12 vs. 5%, respectively; P = 0.023), CYP2A6*5 compared with a Korean population (15 vs. <1%, respectively; P < 0.0001), a Malaysian population (1%; P < 0.0001) and a Chinese population (1%; P < 0.0001); CYP2B6*6 compared with a Korean population (27 vs. 12%; P = 0.002) and a Japanese population (16%; P = 0.021). Pharmacokinetic metrics versus genotype analysis reinforces the view that the predictive value of certain globally common variants (e.g. CYP2D6 single nucleotide polymorphisms) should be evaluated in a population-specific manner.     

Genetic polymorphisms of CYP2C19 influences the response to clopidogrel in ischemic heart disease patients in the South Indian Tamilian population

Background

The antiplatelet activity of clopidogrel is variable among patients suffering from ischemic heart disease. Variation in the cytochrome P450 2C19 (CYP2C19) gene coding for the CYP2C19 enzyme is one of the major determinants of this variable response to clopidogrel. The activity of the CYP2C19 enzyme, which plays a role in the conversion of the prodrug clopidogrel to its active metabolite, is genetically influenced by polymorphisms in its gene. The aim of our study was to evaluate the association of CYP2C19 polymorphisms and the antiplatelet effect of clopidogrel in the South Indian Tamilian population.

Materials and methods

Genotyping and platelet aggregation results of 149 ischemic heart disease patients on clopidogrel maintenance therapy (75 mg daily dose) were analyzed in this study. CYP2C19 polymorphisms were genotyped by the PCR-restriction fragment length polymorphism method. We measured residual platelet activities in these patients on clopidogrel therapy in terms of impedance (expressed as ohms). The study subjects were divided into two metabolizer phenotype groups [group 1: poor/intermediate metabolizers (PM/IM); group 2: extensive/ultra-rapid metabolizers (EM/URM)] based on CYP2C19 genotype, and the residual platelet activities were compared. Higher values of impedance denote increased residual platelet activity.

Results

Poor/intermediate metabolizers had significantly higher impedance values than EM/URM [(median; range) 4.0; 0–13 vs. 2.0; 0–11, respectively; p?=?0.04]. These higher impedance values denote higher residual platelet activities among the carriers of loss-of-function alleles (CYP2C19*2,*3) than among non-carriers. However, residual platelet activities were lower among the carriers of the gain-of-function allele (CYP2C19*17) than among non-carriers, although this difference was not significant.

Conclusion

Patients with CYP2C19 (*2 or *3) genetic polymorphisms had higher residual platelet activities and were associated with a reduced antiplatelet response to clopidogrel. As the South Indian Tamilian population is characterized with higher frequencies of these genetic polymorphisms, our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy.     

The Role of Human CYP2C8 and CYP2C9 Variants in Pioglitazone Metabolism In Vitro

Abstract: The cytochrome P450 enzyme CYP2C8 appears to have a major role in pioglitazone metabolism. The present study was conducted to further clarify the role of individual CYPs and of the CYP2C8/9 polymorphisms in the primary metabolism of pioglitazone in vitro. Pioglitazone (2–400 μM) was incubated with isolated cytochrome P450 enzymes or human liver microsomes, some of them carrying either the CYP2C8*3/*3 genotype (and also the CYP2C9*2/*2 genotype) or the CYP2C8*1/*1 genotype (five samples each). The formation of the primary pioglitazone metabolite M‐IV was monitored by HPLC. Enzyme kinetics were estimated assuming a single binding site. Mean intrinsic clearance of pioglitazone to the metabolite M‐IV was highest for CYP2C8 and CYP1A2 with 58 pmol M‐IV/min/nmol CYP P450/μM pioglitazone each, 53 for CYP2D6*1, 40 for CYP2C19*1, and 34 for CYP2C9*2, respectively. CYP2A6, CYP2B6, CYP2C9*1, CYP2C9*3, CYP2E1, CYP3A4 and CYP3A5 did not form quantifiable amounts of M‐IV. CYP2C8*1/*1 microsomes (25 ± 4 pmol M‐IV/min/mg protein/μM pioglitazone) showed lower intrinsic clearance of pioglitazone than CYP2C8*3/*3 microsomes (35 ± 9, p = 0.04). In all samples, metabolite formation showed substrate inhibition, while pioglitazone did not inhibit CYP2C8‐mediated paclitaxel metabolism. CYP2C8, CYP1A2 and CYP2D6 are major CYPs forming M‐IV in vitro. The higher activity of CYP2C8*3/CYP2C9*2 microsomes may result from a contribution of CYP2C9*2, or from differences in CYP2C8 expression. The evidence for substrate‐specific inhibitory effects of pioglitazone on CYP2C‐mediated metabolism needs to be tested in further studies.