Effects Of CYP2C19 Genetic Polymorphisms Research Articles

Influence of C-reactive protein on the pharmacokinetics of voriconazole in relation to the CYP2C19 genotype: a population pharmacokinetics analysis.

Voriconazole is a broad-spectrum triazole antifungal agent. A number of studies have revealed that the impact of C-reactive protein (CRP) on voriconazole pharmacokinetics was associated with the CYP2C19 phenotype. However, the combined effects of CYP2C19 genetic polymorphisms and inflammation on voriconazole pharmacokinetics have not been considered in previous population pharmacokinetic (PPK) studies, especially in the Chinese population. This study aimed to analyze the impact of inflammation on the pharmacokinetics of voriconazole in patients with different CYP2C19 genotypes and optimize the dosage of administration. Data were obtained retrospectively from adult patients aged ≥16years who received voriconazole for invasive fungal infections from October 2020 to June 2023. Plasma voriconazole levels were measured via high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). CYP2C19 genotyping was performed using the fluorescence in situ hybridization method. A PPK model was developed using the nonlinear mixed-effect model (NONMEM). The final model was validated using bootstrap, visual predictive check (VPC), and normalized prediction distribution error (NPDE). The Monte Carlo simulation was applied to evaluate and optimize the dosing regimens. A total of 232 voriconazole steady-state trough concentrations from 167 patients were included. A one-compartment model with first order and elimination adequately described the data. The typical clearance (CL) and the volume of distribution (V) of voriconazole were 3.83L/h and 134L, respectively. The bioavailability was 96.5%. Covariate analysis indicated that the CL of voriconazole was substantially influenced by age, albumin, gender, CRP, and CYP2C19 genetic variations. The V of voriconazole was significantly associated with body weight. An increase in the CRP concentration significantly decreased voriconazole CL in patients with the CYP2C19 normal metabolizer (NM) and intermediate metabolizer (IM), but it had no significant effect on patients with the CYP2C19 poor metabolizer (PM). The Monte Carlo simulation based on CRP levels indicated that patients with high CRP concentrations required a decreased dose to attain the therapeutic trough concentration and avoid adverse drug reactions in NM and IM patients. These results indicate that CRP affects the pharmacokinetics of voriconazole and is associated with the CYP2C19 phenotype. Clinicians dosing voriconazole should consider the patient's CRP level, especially in CYP2C19 NMs and IMs.

Effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of lacosamide in Korean patients with epilepsy.

Many pharmacokinetic studies of lacosamide (LCM) have been reported, but no large-scale clinical study has been conducted on genetic polymorphisms that affect the metabolism of LCM. Therefore, we designed a pharmacogenetic study of LCM to explore the effect of genetic polymorphisms on serum LCM concentration. We evaluated the pharmacodynamic characteristics of LCM, including clinical efficacy and toxicity. Adult patients with epilepsy who received LCM at Seoul National University Hospital were enrolled. Blood samples were obtained from 115 patients taking LCM for more than 1 month with unchanged doses and were used to analyze the serum LCM concentration, the concentration/dose (C/D) ratio and the single nucleotide polymorphisms (SNPs) of the cytochrome P450 (CYP)2C9 and CYP2C19 genes. In addition, clinical information-including efficacy, toxicity, and concomitant drugs-was collected. The serum LCM concentration showed a linear correlation with the daily dose (r=.66, p < .001). In genetic analysis, 43 patients (38.7%) were extensive metabolizers (EMs), 51 (45.9%) were intermediate metabolizers (IMs), and 17 (15.3%) were poor metabolizers (PMs). In the group comparison, mean serum concentrations and the C/D ratio showed significant differences between the three groups (p=.01 and p < .001, respectively). The C/D ratios of IM (27.78) and PM (35.6) were 13% and 39% higher than those of EM (25.58), respectively. In the pharmacodynamic subgroup analysis, patients in the ineffective LCM group had significantly lower serum concentrations (6.39 ± 3.25 vs. 8.44 ± 3.68 μg/ml, p=.024), whereas patients with adverse events had higher serum concentrations than those without adverse events (11.03 ± 4.32 vs. 7.4 ± 3.1μg/ml, p < .001). Based on this, we suggest a reference range for LCM in the Korean population (6-9μg/ml). Genetic polymorphisms of the CYP2C19 gene affect the serum LCM concentration. Because efficacy and toxicity are apparently related to serum LCM levels, the genetic phenotype of CYP2C19 should be considered when prescribing LCM for patients with epilepsy.

Effect of CYP2C19 genetic polymorphism on the pharmacodynamics and clinical outcomes for patients treated with ticagrelor: a systematic review with qualitative and quantitative meta-analysis

BackgroundStudies show inconsistent results regarding the impact of CYP2C19 genotype on the pharmacodynamics (PD) and clinical outcomes of ticagrelor. With the implementation of genotype-guided individualized antiplatelet therapy, the association between CYP2C19 polymorphism and the efficacy and safety of ticagrelor for patients is still worthy of exploring and studying.MethodsThis systematic review protocol has been registered in the PROSPERO network (No. CRD 42020158920). Electronic databases of PubMed, EmBase, and the Cochrane Library were systematically searched from inception to January 6th, 2022 to select studies investigating the impact of CYP2C19 genotype on PD and clinical outcomes of ticagrelor. The results were presented as odds ratio (OR) or weight mean difference with its 95% confidence interval (CI) by using the random-effects model. Trial sequential analysis (TSA) was used to control risk of random errors and detect the robustness of outcomes.ResultsEight studies recruited a total of 6405 patients treated with ticagrelor. Mostly trials reported no significant effect of any or no CYP2C19 loss-of-function (LOF) allele (*2 or *3) on all the endpoints. Compared with no LOF allele carriers, subgroup analysis suggested any LOF allele in Asian patients was associated with a significant decreased risk of bleeding events (OR: 0.41; 95% CI: 0.22–0.75; P = 0.004). Furthermore, any LOF allele carriers didn’t yield any impact on the risk of MACEs (OR: 1.11; 95% CI: 0.76–1.64; P = 0.586), stroke (OR: 1.71; 95% CI: 0.99–2.96; P = 0.054), definite stent thrombosis (OR: 0.88; 95% CI: 0.17–4.60; P = 0.882), bleeding (OR: 0.63; 95% CI: 0.27–1.46; P = 0.281), myocardial infarction (OR: 0.81; 95% CI: 0.30–2.20; P = 0.682), and revascularization (OR: 0.81; 95% CI: 0.33–2.00; P = 0.649) in all patients. The results of TSA were indicated that more further trials would be required.ConclusionsThis qualitative and quantitative study suggested Asian patients carrying any CYP2C19 LOF allele might have a lower risk of bleeding events comparing with no LOF allele carriers when treated with ticagrelor. However, we did not prove an important role of CYP2C19 genotype on the risk of PD and clinical endpoints in the whole cohort. In future, more large-scale prospective studies and more different ethnic populations should be included.

Analysis of Combined Effect of CYP2C19 Genetic Polymorphism and Proton Pump Inhibitors Coadministration on Trough Concentration of Voriconazole.

PurposeTo analyze the combined effect of CYP2C19 genetic polymorphism and PPIs coadministration on voriconazole trough concentration (VCZ-Ctrough) in Chinese patients with hematological disorders.Patients and MethodsA prospective observational study involved 250 plasma samples from 114 adult patients receiving voriconazole with or without PPIs were analyzed. Demographics and clinical characteristics were obtained from patient’s records. A validated LC-MS/MS was used to quantify the plasma VCZ-Ctrough. Genotyping for CYP2C19*2 and CYP2C19*3 variant alleles was performed by PCR-RFLP followed by DNA sequencing. The combined total score (from 2 to 5) was calculated for each patient. The higher the score, the lesser the metabolism of the patient.FindingsFifty percent of patients administered with voriconazole were coadministered with PPIs, predominantly omeprazole or esomeprazole. Patients exhibiting CYP2C19 poor metabolizer phenotype showed a significantly higher median VCZ-Ctrough, (4.31µg/mL [IQR, 1.64µg/mL–7.36µg/mL]) than patients with normal metabolizer (1.38µg/mL, [IQR, 0.79µg/mL–2.14µg/mL], p < 0.0001). Similarly, patients co-administration with PPIs had higher median VCZ-Ctrough (2.86µg/mL [IQR 1.33µg/mL–4.66µg/mL]), than PPIs non-users (1.71µg/mL, [IQR, 0.86µg/mL–3.48µg/mL], p = 0.001). However, we noted that the median VCZ-Ctrough for each factor was ranging within the normal recommended therapeutic range in the Chinese population (0.5µg/mL–5µg/mL). But when the two factors were combined, the median VCZ-Ctrough was steadily increasing as the metabolic capacity (reflected by combined total score) was increasing. Importantly, the median VCZ-Ctrough in PM/PPIs user (total score 5) was significantly elevated to supra-therapeutic levels compared to NM/PPI non-user group (total score 2) (5.83µg/mL [IQR, 2.19µg/mL–9.51µg/mL] versus 1.13µg/mL [IQR, 0.67µg/mL–1.82µg/mL]), respectively, P < 0.0001. Furthermore, we observed that the elevation of median VCZ-Ctrough to supra-therapeutic levels was largely contributed by omeprazole or esomeprazole compared to lansoprazole or pantoprazole.ConclusionCoadministration with PPIs significantly increased voriconazole trough concentrations and there was an additive effect in CYP2C19 PMs, who were most likely to have supra-therapeutic levels.

Effects of CYP2C19 genetic polymorphism on the steady-state concentration of citalopram in patients with major depressive disorder.

Citalopram is commonly prescribed to patients suffering from major depressive disorder. Some of them do not respond adequately to therapy with citalopram, while many of them experience type A adverse drug reactions. Current research revealed that CYP2C19 isoenzyme is involved in the biotransformation of citalopram. The objective of our study was to investigate the impact of 681G>A polymorphism of the CYP2C19 gene on the efficacy, safety and the concentration/dose indicator of citalopram. Our study enrolled 130 patients with major depressive disorder and comorbid alcohol use disorder (average age-38.7 ± 14.1 years). Therapy regimen included citalopram in an average daily dose of 31.1 ± 14.4 mg per week. Therapy efficacy and safety were evaluated using the international psychometric scales. For genotyping, we performed the real-time polymerase chain reaction. Our findings revealed the statistically significant results in terms of the treatment efficacy evaluation (HAMD scores at the end of the treatment course): (GG) 8.0 [8.0; 9.0] and (GA) 10.0 [9.0; 11.0], p < 0.001. In the safety profile (the UKU scores), the statistical significance was also obtained: (GG) 3.0 [3.0; 4.0] and (GA) 5.0 [4.0; 5.0], p < 0.001. We revealed a statistical significance for concentration/dose indicator of citalopram in patients with different genotypes: (GG) 2.543 [1.659; 4.239] and (GA) 4.196 [2.643; 5.753], p < 0.001). The effect of CYP2C19 genetic polymorphism on the efficacy and safety profiles of citalopram was demonstrated in a group of 130 patients with major depressive disorder.

Effects of genetic polymorphisms of CYP2C19 on the pharmacokinetics of zolpidem.

Zolpidem is indicated for the short-term treatment of insomnia and it is predominantly metabolized by CYP3A4, and to a lesser extent by CYP2C19, CYP1A2, and CYP2C9. Therefore, we evaluated the effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of zolpidem in healthy male subjects. Thirty-two male subjects were recruited and all subjects were classified into three groups according to their genotypes: CYP2C19EM (CYP2C19*1/*1, n = 12), CYP2C19IM (CYP2C19*1/*2 or *1/*3, n = 10), and CYP2C19PM (CYP2C19*2/*2, *2/*3 or *3/*3, n = 10). The pharmacokinetic parameters of zolpidem were compared in three CYP2C19 genotype groups after zolpidem administration with or without a CYP3A4 inhibitor at steady-state concentration. Plasma concentrations of zolpidem were determined up to 12h after drug administration by liquid chromatography-tandem mass spectrometry method. The maximum plasma concentration (Cmax) differed, but mean total area under the plasma concentration-time curve (AUCinf), half-life (t1/2), and apparent oral clearance (CL/F) of zolpidem administered alone did not significantly differ among the three different CYP2C19 genotype groups. Furthermore, when zolpidem was administered with a CYP3A4 inhibitor at steady-state concentration, there were no significant differences in any of the pharmacokinetic parameters of zolpidem in relation to CYP2C19 genotypes. In conclusion, we did not find any evidence for the impact of CYP2C19 genetic polymorphisms on the pharmacokinetic parameters of zolpidem.

Effects of CYP2C19 Genetic Polymorphisms on the Pharmacokinetic and Pharmacodynamic Properties of Clopidogrel and Its Active Metabolite in Healthy Chinese Subjects

PurposeSome studies in the white population have shown that carriers of at least 1 loss-of-function allele in the gene that encodes the cytochrome P-450 2C19 isozyme (CYP2C19) have lower levels of the clopidogrel active metabolite (CAM) and a reduced antiplatelet effect of clopidogrel. However, data are limited regarding the association between CYP2C19 genetic variants and exposure to CAM and on the pharmacodynamic properties of CAM in the Chinese population. Data from the white population cannot be extrapolated to the Chinese population because of the marked interethnic differences in CYP2C19 variants. This study was aimed to investigate the influence of CYP2C19 genetic polymorphisms on the pharmacokinetic properties of CAM and the antiplatelet effect of clopidogrel in healthy Chinese volunteers, and to provide evidence for the role of a CYP2C19 genotyping test in predicting the antiplatelet effect of clopidogrel in the Chinese population. MethodsTwenty healthy subjects received a single 300-mg dose of clopidogrel and were assigned to 1 of 3 groups according to CYP2C19 genotype: CYP2C19 *1/*1 (normal metabolizers [NM]; n = 8), CYP2C19 *1/*2 or *3 (intermediate metabolizers [IM]; n = 10) and CYP2C19 *2/*2 or *3 and *3/*3 (poor metabolizers [PM]; n = 2). Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration. The plasma concentrations of clopidogrel and CAM were analyzed by LC-MS/MS, and adenosine diphosphate–induced platelet aggregation was measured by light-transmittance aggregometry. FindingsThere were no significant differences in Cmax and AUC0–t of clopidogrel prodrug in the NM group compared with the IM and PM groups. The mean CAM Cmax value was significantly higher in the NM group than in IM and PM groups (45.39 [12.57] vs 29.15 [7.92] ng/mL [P = 0.003] and 19.55 [2.19] ng/mL [P = 0.004], respectively). The mean CAM AUC0–t value was significantly higher in the NM group than in the IM and PM groups (61.05 [21.63] vs 37.67 [11.01] ng · h/mL [P = 0.007] and 27.08 [2.72] ng · h/mL [P = 0.016]). The NM group exhibited a significantly higher percentage of inhibition of platelet aggregation than did the IM or PM group (P = 0.001). The correlations between the pharmacokinetic properties (Cmax, AUC0–t) of CAM and the pharmacodynamic data (maximal and inhibition of platelet aggregation) were significant (both, Pearson r > 0.5 and P < 0.01). ImplicationIn these healthy Chinese subjects, carriers of CYP2C19 loss-of-function allele(s) had significantly reduced exposure of CAM and decreased levels of inhibition of platelet aggregation with clopidogrel; these genotypes therefore might be a determinant for the formation of CAM and its antiplatelet effects. Study identifier: ChiCTR-OCH-14004382.

Therapeutic Drug Monitoring of Voriconazole in the Management of Invasive Fungal Infections: A Critical Review

The broad-spectrum triazole antifungal agent voriconazole is highly efficacious against invasive fungal infections (IFIs) caused by Aspergillus spp. and Candida spp. IFIs are associated with high rates of mortality and morbidity, especially in vulnerable populations such as patients with hematopoietic stem cell transplant as well as other immunocompromised patients. Efficacy of voriconazole in these patients is critical to ensure positive outcomes and reduce mortality. However, a major limitation of voriconazole is the risk of adverse events such as hepatotoxicity and neurotoxicity. As such, therapeutic drug monitoring (TDM) has been suggested as a mechanism to optimize both efficacy and safety. The aim of this review was to summarize and evaluate evidence from the primary literature that assessed TDM outcomes for voriconazole as well as evaluate the association between CYP2C19 polymorphism and the clinical outcomes of voriconazole. Findings showed associations for both efficacy and safety outcomes with measurement of drug concentrations, yet exact targets or thresholds remain unclear. As such, TDM should be reserved for those patients not responding to therapy with voriconazole or those experiencing adverse drug reactions. Future studies should attempt to further define these populations within controlled settings. Studies that evaluated the effect of CYP2C19 genetic polymorphism on clinical outcomes found no significant relationship between CYP2C19 genotype and hepatotoxicity. These negative findings may be due to lack of power, use of phenotypes not well-defined, and the presence of other interacting factors that may impact voriconazole pharmacokinetics. Future well-designed studies are warranted to confirm these findings.

Helicobacter pylori infection in pediatrics.

This review concerns important pediatric studies published from April 2013 to March 2014. New data on pathogenesis have demonstrated that Th1 type cytokine secretion at the gastric level is less intense in children compared with adults. They have also shown that the most significant risk factor for Helicobacter pylori infection is the parents' origin and frequency of childcare in settings with a high prevalence of infection. A new hypothesis on the positive relationship between childhood H.pylori infection and the risk of gastric cancer in adults has been suggested which calls for an implementation of preventive programs to reduce the burden of childhood H.pylori infection in endemic areas. Several studies have investigated the role of H.pylori infection in iron-deficiency anemia, and results support the role of the bacterium in this condition. Antibiotic resistance is an area of intense research with data confirming an increase in antibiotic resistance, and the effect of CYP2C19 genetic polymorphism on proton-pump inhibitor metabolism should be further investigated as cure rates are lower in extensive metabolizers. Studies confirmed that probiotic supplementation may have beneficial effects on eradication and therapy-related side effects, particularly diarrhea in children.

Cure rate of Helicobacter pylori infection in Egyptian children related to CYP2C19 gene polymorphism

This study was done in order to investigate the effect of CYP2C19 genetic polymorphism on the cure rate of children who received proton pump inhibitors (PPI)-based triple therapy for treating Helicobacter pylori (H. pylori) infection. Participants included 100 children with H. pylori-positive gastritis diagnosed by endoscopy and biopsy in addition to H. pylori stool antigen test. Cure rate was assessed after 1month of completion of a triple treatment course for 14days. CYP2C19 polymorphism was analyzed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results showed that cases with a CYP2C19 genotypic status consistent with the heterozygote extensive metabolizers (HetEMs) had a higher cure rate of H. pylori when compared with the homozygote extensive metabolizers (HomEMs) although it was statistically nonsignificant (84.6 vs. 69.2). In addition, the poor metabolizers (PMs) had a higher cure rate compared with those of the HomEMs which was also statistically nonsignificant (77.8 vs. 69.2). The cure rate was also higher among both the groups of HetEMs and PMs combined together compared to the HomEMs (OR = 2.15, p > 0.05). Comparing cases regarding their age, gender, and severity of H. pylori gastritis revealed a better cure rate in the age group >10years, in females and in mild and moderate cases than other cases although statistically nonsignificant. The higher cure rate of H. pylori infection using the triple therapy for 2weeks among HetEMs and PMs cases compared to the HomEMs might warrant a need for a therapy augmentation or modification for the HomEMs.

CYP2C19 Genetic Polymorphism, Rabeprazole and Esomeprazole Have No Effect on the Anti-Platelet Action of Clopidogrel

Purpose: To investigate the effect of CYP2C19 genetic polymorphism and concomitant use of rabeprazole or esomeprazole on the anti-platelet effect of clopidogrel in vitro. Methods: Patients receiving a stable dose of clopidogrel 75 mg with or without rabeprazole or esomeprazole for > 2 weeks were recruited. Genotyping for CYP2C19 and VASP testing using flow cytometry to measure platelet reactivity index (PRI) were performed. A detailed questionnaire regarding the indication and duration of use of clopidogrel and PPI therapy was completed on all patients including a detailed concomitant drug history. Results: 239 consecutive patients (176M and 63F; mean age = 67.1±12.0) were enrolled after informed consent. 92 patients were on clopidogrel without concomitant PPI therapy (C group), 94 were on clopidogrel + rabeprazole (CR group), and 53 on clopidogrel + esomeprazole (CE group). The mean number of concomitant medications in addition to clopidogrel was 5.7± 3.0. The main indications for clopidogrel were cardiac, neurologic, and peripheral vascular disease (71.5, 25.5, and 2.5% respectively) and the mean duration of clopidogrel therapy was 33.1 ± 40.4 months. The indications for PPI use were considered appropriate in 30.6% of users. On CYP2C19 genotyping, 194 patients did not have loss of function polymorphism (LOF) while 45 had LOF (43 heterozygous and 2 homozygous mutant for CYP2C19*2).The mean PRI was 20.7±21.9% in the clopidogrel group, 19.1±20.9% in the CR group, and 24.5±22.9% in the CE group (p=0.386). High-on-treatment Platelet Reactivity (HPR) defined as PRI>50%, was observed in 12 (13.0%), 13 (13.8%), and 10 (18.9%) patients on C, CR, CE, respectively (p=0.608). A PRI of >30% was noted in 23 (25.0%), 22 (23.4%), and 20 (37.7%) patients on C, CR, CE respectively (p=0.144). In participants with no LOF alleles (194/239 or 81.2% of study population), a PRI>30% was noted in 21.9%, 22.1% and 38.6% of the C, CR and CE groups patients respectively (p=0.085) (p-value of 0.052 between the C and CE groups and p-value of 0.051 between the CR and CE groups). On multivariate logistic regression, neither the presence of CYP2C19 LOF alleles nor the use of esomeprazole or rabeprazole were associated with HPR. Conclusion: 14.4% of individuals on clopidogrel monotherapy have an unsatisfactory in vitro platelet inhibition independent of CYP2C19 polymorphism. Neither CYP2C19 LOF alleles, nor esomeprazole nor rabeprazole had a significant effect on the anti-platelet action of clopidogrel in vitro, although there was a trend for a relatively reduced platelet inhibition with esomeprazole compared to rabeprazole users or non-PPI users in patients without CYP2C19 LOF mutations.

Effect of CYP2C19 Genetic Polymorphism on Pharmacokinetics and Pharmacodynamics and Pharmacodynamics of a New Proton Pump Inhibitor, Ilaprazole

It is well known that the CYP2C19 genetic polymorphism influences the pharmacokinetics and pharmacodynamics of proton pump inhibitors (PPIs), but no report has addressed the effects on ilaprazole, a newly developed PPI. To investigate the effects of the CYP2C19 genetic polymorphism on the disposition and pharmacodynamics of ilaprazole, multiple doses of once-daily 10 mg ilaprazole were repeatedly administered for 7 days to 27 healthy Korean participants, comprising 9 homozygous CYP2C19 extensive metabolizers (homo EMs), 10 heterozygous EMs (hetero EMs), and 8 homozygous poor metabolizers (PMs). The plasma concentration and pharmacodynamic response were measured in the last dose interval. Each genotype group was matched for gender and thus was composed of 4 male and 4 female participants when the analysis was conducted. The pharmacokinetic parameters estimated from the plasma concentrations of ilaprazole and its metabolite ilaprazole sulfone, the serum gastrin level, and the 24-hour intragastric pH were compared among the CYP2C19 genotype groups. No statistically significant differences in the maximum plasma concentration at steady state(C(ss,max)) and the area under the concentration-time curve from zero to 24 hours (AUC(τ)) of ilaprazole and ilaprazole sulfone were observed among the homo EM, hetero EM, and PM CYP2C19 genotypes. In addition, the mean 24-hour intragastric pH, the percentage of time at pH >4, and the AUC(τ) of serum gastrin showed no significant differences among the CYP2C19 genotype groups. The data suggests that the pharmacokinetics and pharmacodynamics of ilaprazole are not significantly influenced by the CYP2C19 genetic polymorphism in healthy participants.

Drug–drug interaction of rabeprazole and clopidogrel in healthy Chinese volunteers

This study was aimed to determine the impact of rabeprazole (RBRZ) on the antiplatelet efficacy of clopidogrel (CPG) in healthy Chinese volunteers, and further to predict the effect of CYP2C19 genetic polymorphism on the efficacy of rabeprazole and clopidogrel. The open-label, two period cross-over study was conducted in 20 healthy Chinese subjects with different CYP2C19 genotypes receiving clopidogrel, rabeprazole or the two drugs, respectively. All the volunteers were divided into two groups, poor metabolizers (PMs) and extensive metabolizers (EMs), depending on CYP2C19 genotypes. Blood samples were collected at baseline and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h after administration. The plasma concentrations of rabeprazole and clopidogrel were analyzed by LC-MS/MS and ADP-induced platelet aggregation was detected by the optical turbidimetric method. There were no significant differences in the mean plasma concentration-time curves of clopidogrel (CPG), the inactive metabolite clopidogrel carboxylic acid (CPG-CA), the active metabolite clopidogrel-MP-Derivative (MP-AM), and rabeprazole (RBRZ) according to the co-administration of CPG and RBRZ. There were no major changes in the pharmacokinetics of CPG and RBRZ. The maximal ADP-induced platelet aggregation (2 μmol/L) was decreased in EMs compared with PMs. Co-administration of rabeprazol and clopidogrel did not affect the antiplatelet efficacy of clopidogrel. The CYP2C19 genetic polymorphism may impact the efficacy of clopidogrel.

Effects of cytochrome P450 (CYP)2C19 polymorphisms on pharmacokinetics of phenobarbital in neonates and infants with seizures

BackgroundPhenobarbital (PB), commonly used as the preferred treatment for neonatal seizure, is a drug that requires careful dose adjustments based on therapeutic drug monitoring. It has been reported that PB...

Evaluation of the effects of 18 non-synonymous single-nucleotide polymorphisms of CYP450 2C19 on in vitro drug inhibition potential by a fluorescence-based high-throughput assay

To comprehensively understand the effects of CYP2C19 genetic polymorphisms on inhibition-based drug–drug interactions (DDIs), 18 human CYP2C19 non-synonymous single-nucleotide polymorphic variants and the wild-type isoform (CYP2C19.1A) were expressed in yeast cells. Using a fluorescence-based high-throughput method, the kinetic constants of these variants, as well as the inhibition constants for 10 drugs, were determined.CYP2C19.5B and CYP2C19.6 showed no activity towards CEC (3-cyano-7-ethoxycoumarin) O-deethylation. CYP2C19.8, CYP2C19.9, CYP2C19.10, CYP2C19.16, CYP2C19.19, E122A and A161P* (an allele containing both A161P and I331V) exhibited significantly reduced catalytic activities compared with CYP2C19.1A. The inhibition assay showed that the CYP2C19 genotype significantly affected the in vitro drug inhibition potential. Although the effect on drug inhibition potential is genotype- and inhibitor-dependent, there was an obvious trend: drugs tended to exhibit higher IC50 values (i.e. decreased inhibition potential) towards variants with reduced activity compared with variants with normal activity. This indicated that patients with reduced-function alleles may be less susceptible to CYP2C19-related DDIs.In this study, we provided the first in vitro evidence of CYP2C19 genotype-dependent effects on drug inhibition potential. This work greatly extends our understanding of the functional consequences of CYP2C19 genetic polymorphisms, and thus should prove valuable for CYP2C19 genotype-based therapy.

Effect of CYP2C19 genetic polymorphism on pharmacokinetics of phenytoin and phenobarbital in Japanese epileptic patients using Non-linear Mixed Effects Model approach

To clarify the effect of genetic polymorphism of CYP2C19 on pharmacokinetics of phenytoin and phenobarbital using a Non-linear Mixed Effects Modelling analysis in Japanese epileptic patients. A total of 326 serum phenytoin concentrations were collected from 132 patients, and a total of 144 serum phenobarbital concentrations were collected from 74 patients during their clinical routine care. The maximal elimination rate of phenytoin decreased by 10.2% in patients with CYP2C19*1/*2 compared with patients with normal CYP2C19. The Michaelis-Menten constants in the patients with CYP2C19*1/*3 and the poor metabolizers of (CYP2C19*2/*2 or *2/*3 or *3/*3) were 27% and 54% higher than those for the patients with normal CYP2C19, respectively. The total body clearance of phenobarbital decreased by 19.3% in patients with CYP2C19*1/*3 or the poor metabolizers of CYP2C19 compared with patients with normal CYP2C19 or with CYP2C19*1/*2. These findings indicated that the genetic polymorphisms of CYP2C19 contribute to the pharmacokinetic variability of phenytoin and phenobarbital, the poor metabolizers of CYP2C19, which are relatively common in Asian groups.