&lt;p&gt;&lt;em&gt;CYP2C19&lt;/em&gt;*&lt;em&gt;2&lt;/em&gt; Polymorphism Is Associated with Impaired Oral Clearance of Gliclazide in Healthy Chinese&lt;/p&gt;

Chow, Elaine; Poon, Emily; Fok, Benny S. P.; Chan, Juliana C.N.; Tomlinson, Brian

doi:10.2147/pgpm.s226200

Cited by 9 publications

(5 citation statements)

References 24 publications

(32 reference statements)

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“…The results of this analysis in real-world settings support our previous pharmacokinetic studies regarding the higher plasma level of gliclazide in CYP2C19 PMs. 19 Here, CYP2C19*2 also had pharmacodynamic effects on short-term HbA1c response and longterm treatment failure in patients receiving SU monotherapy or dual therapy of SU and metformin. Patients who were CYP2C19 PMs were 1.5 times more likely to achieve HbA1c target within 18 months of SU initiation.…”

Section: Discussionmentioning

confidence: 89%

“…18 In a pharmacokinetic study of healthy Chinese subjects, we showed that CYP2C19*2/*2 was associated with 2-fold increase in total plasma gliclazide area-under-the-curve and plasma half-life with 50% reduction in oral drug clearance compared with CYP2C19 EMs. 19 Despite the common use of SUs in Asians, there are no largescale pharmacogenetic studies examining the effect of CYP2C19*2 or CYP2C19*3 polymorphisms on SU treatment response or risk of hypoglycemia in this population. We therefore investigated the associations of CYP2C19 loss-of-function polymorphisms with SU treatment failure, SU efficacy, and risk of hypoglycemia among incident SU users.…”

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confidence: 99%

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CYP2C19 Loss‐of‐function Polymorphisms are Associated with Reduced Risk of Sulfonylurea Treatment Failure in Chinese Patients with Type 2 Diabetes

Wang

Yang

Shi

et al. 2021

Clin Pharma and Therapeutics

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Sulfonylureas (SUs) are predominantly metabolized by cytochrome p450 2C9 (CYP2C9) and cytochrome p450 2C19 (CYP2C19) enzymes. CYP2C9 polymorphisms are associated with greater treatment response and hypoglycemic risk in SU users. However, there are no large scale pharmacogenetic studies investigating the effect of loss-of-function alleles CYP2C19*2 and CYP2C19*3, which occur frequently in East Asians. Retrospective pharmacogenetic analysis was performed in 11,495 genotyped patients who were enrolled in the Hong Kong Diabetes Register between 1995 and 2017, with follow-up to December 31, 2019. The associations of CYP2C19 polymorphisms with SU treatment failure, early HbA1c response, and severe hypoglycemia were analyzed by Cox regression or logistic regression assuming an additive genetic model. There were 2341 incident SU users that were identified (mean age 59 years, median diabetes duration 9 years), of which 324 were CYP2C19 poor metabolizers (CYP2C19 *2/*2 or *2/*3 or *3/*3). CYP2C19 poor metabolizers had lower risk of SU treatment failure (hazard ratio 0.83, 95% confidence interval (CI) 0.72-0.97, P = 0.018) and were more likely to reach the HbA1c treatment target < 7% (odds ratio 1.52, 95% CI 1.02-2.27, P = 0.039) than wild-type carriers (CYP2C19 *1/*1) following adjustment for multiple covariates. There were no significant differences in severe hypoglycemia rates among different CYP2C19 genotype groups. CYP2C19 polymorphisms should be considered during personalization of SU therapy.

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

CYP2C19 Loss‐of‐function Polymorphisms are Associated with Reduced Risk of Sulfonylurea Treatment Failure in Chinese Patients with Type 2 Diabetes

Wang

Yang

Shi

et al. 2021

Clin Pharma and Therapeutics

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“…In many studies, most CYP2C19 mutations involved three common alleles in the Chinese Han population, namely CYP2C19 *2,*3, and *17 ( Chow et al., 2019 ). The current study was conducted on the Henan Chinese Han patient population, and the allele frequencies for CYP2C19 *2,*3, and *17 were found to be 30.8%, 3.8%, and 1.3%, respectively.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a mathematical prediction model for voriconazole stable maintenance dose: a prospective study

Zhou¹,

Li²,

Li³

et al. 2023

Front. Cell. Infect. Microbiol.

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BackgroundIn patients with invasive fungal infection (IFI), the steady-state serum trough concentration (Cmin) of voriconazole (VCZ) is highly variable and can lead to treatment failure (Cmin < 0.5 mg/L) and toxicity (Cmin ≥ 5.0 mg/L). However, It remains challenging to determine the ideal maintenance dose to achieve the desired Cmin level quickly.AimsThis randomized, prospective observational single-center study aimed to identify factors affecting VCZ-Cmin and maintenance dose and create an algorithmic model to predict the necessary maintenance dose. MeThe study enrolled 306 adult IFI patients, split into two groups: non-gene-directed (A) (where CYP2C19 phenotype is not involved in determining VCZ dose) and gene-directed (B) (where CYP2C19 phenotype is involved in determining VCZ dose).ResultsResults indicated that CYP2C19 genetic polymorphisms might significantly impact VCZ loading and maintenance dose selection. CYP2C19 phenotype, C-reaction protein (CRP), and average daily dose/body weight were significant influencers on VCZ-Cmin, while CYP2C19 phenotype, CRP, and body weight significantly impacted VCZ maintenance dose. A feasible predictive formula for VCZ stable maintenance dose was derived from the regression equation as a maintenance dose (mg) =282.774-0.735×age (year)+2.946×body weight(Kg)-19.402×CYP2C19 phenotype (UM/RM/NM:0, IM:1, PM:2)-0.316×CRP (mg/L) (p < 0.001).DiscussionDiThis formula may serve as a valuable supplement to the Clinical Pharmacogenetics Implementation Consortium (CPIC®) guideline for CYP2C19 and VCZ therapy, especially for IFI patients with highly variable inflammatory cytokines during VCZ therapy.

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“…However, microsomes were prepared from six human livers which were not genotyped for CYP2C19 polymorphisms. Furthermore, later in vivo studies showed that gliclazide PK is affected mainly by CYP2C19 polymorphisms [ 11 , 12 , 55 ]. Based on these PK clinical studies in individuals with different CYP2C19 and CYP2C9 genotypes [ 11 , 12 ], it was estimated that the contribution of CYP2C9 to gliclazide metabolism is around 24%, and of CYP2C19 around 76% [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Interaction between Omeprazole and Gliclazide in Relation to CYP2C19 Phenotype

Dujić

Cvijić

Elezovic

et al. 2021

JPM

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The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed PBPK models were verified using in vivo pharmacokinetic profiles obtained from a clinical trial on omeprazole-gliclazide interaction in healthy volunteers, CYP2C19 normal/rapid/ultrarapid metabolizers (NM/RM/UM). In addition, the association of omeprazole cotreatment with gliclazide-induced hypoglycemia was explored in 267 patients with type 2 diabetes (T2D) from the GoDARTS cohort, Scotland. The PBPK simulations predicted 1.4–1.6-fold higher gliclazide area under the curve (AUC) after 5-day treatment with 20 mg omeprazole in all CYP2C19 phenotype groups except in poor metabolizers. The predicted gliclazide AUC increased 2.1 and 2.5-fold in intermediate metabolizers, and 2.6- and 3.8-fold in NM/RM/UM group, after simulated 20-day dosing with 40 mg omeprazole once and twice daily, respectively. The predicted results were corroborated by findings in patients with T2D which demonstrated 3.3-fold higher odds of severe gliclazide-induced hypoglycemia in NM/RM/UM patients concomitantly treated with omeprazole. Our results indicate that omeprazole may increase exposure to gliclazide and thus increase the risk of gliclazide-associated hypoglycemia in the majority of patients.

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<p><em>CYP2C19</em>*<em>2</em> Polymorphism Is Associated with Impaired Oral Clearance of Gliclazide in Healthy Chinese</p>

Cited by 9 publications

References 24 publications

CYP2C19 Loss‐of‐function Polymorphisms are Associated with Reduced Risk of Sulfonylurea Treatment Failure in Chinese Patients with Type 2 Diabetes

CYP2C19 Loss‐of‐function Polymorphisms are Associated with Reduced Risk of Sulfonylurea Treatment Failure in Chinese Patients with Type 2 Diabetes

Establishment of a mathematical prediction model for voriconazole stable maintenance dose: a prospective study

Interaction between Omeprazole and Gliclazide in Relation to CYP2C19 Phenotype

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