Impact of POR*28 on the clinical pharmacokinetics of CYP3A phenotyping probes midazolam and erythromycin

Elens, Laure; Nieuweboer, Annemieke J.M.; Clarke, Stephen; Charles, Kellie A.; Graan, Anne-Joy M. de; Haufroid, Vincent; Gelder, Teun van; Mathijssen, Ron H.J.; Schaik, Ron H.N. van

doi:10.1097/fpc.0b013e32835dc113

Cited by 36 publications

(20 citation statements)

References 37 publications

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“…POR*28 C>T polymorphism was associated with CYP3A activity. 28,29) Our results did not show any significant effect of POR*28, CYP3A4*1G or CYP3A5*3 variants on the disposition of amlodipine in essential hypertensive patients. The major reason is that a study involving a larger population sample is needed to take into account genetic linkage analysis between CYP3A4*1G and CYP3A5*3 on the biotransformation of amlodipine.…”

Section: Discussioncontrasting

confidence: 51%

ABCB1 Polymorphism and Gender Affect the Pharmacokinetics of Amlodipine in Chinese Patients with Essential Hypertension: A Population Analysis

Zuo

Zhang

Yuan

et al. 2014

Drug Metabolism and Pharmacokinetics

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The effects of genetic polymorphisms of ABCB1 C3435T, POR*28, CYP3A4*1G and CYP3A5*3 variants and gender relating to metabolism on the exposure and response of amlodipine in Chinese hypertensive patients were determined. Population pharmacokinetic analyses were performed on data which were collected prospectively from 60 Chinese patients with mild to moderate essential hypertension [age range 40-74 years, males (n = 31), females (n = 29)] receiving oral racemic amlodipine for 4 weeks. Blood pressure was evaluated at the end of weeks 0 and 4. Blood samples were collected in heparinized tubes at the following times: 0, 2, 6, and 24 h on about day 28 after administration of amlodipine. A one-compartment model with first-order elimination and absorption best described the amlodipine pharmacokinetic data. ABCB1 3435 genetic polymorphism and gender affect the amlodipine oral clearance (CL/F). CL/F (L/h) = 28.8 × (1 + GNDR)(-0.531) × (ABCB1 C3435T) where GNDR = 0 and 1 are for male and female, respectively. The CL/F value in a male patient with the ABCB1 3435CC or CT genotype is 28.8 L/h. Lower CL/F and higher exposure occurs in female subjects with the ABCB1 3435CC or CT genotype who have greater decreases in blood pressure after treatment with amlodipine. The results may help to improve the efficacy and tolerability of amlodipine in essential hypertensive patients.

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Section: Discussioncontrasting

confidence: 51%

ABCB1 Polymorphism and Gender Affect the Pharmacokinetics of Amlodipine in Chinese Patients with Essential Hypertension: A Population Analysis

Zuo

Zhang

Yuan

et al. 2014

Drug Metabolism and Pharmacokinetics

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“…One coding variant in POR gene, termed POR*28 (rs1057868; A503V) has a functional impact in that it increases the activity of POR, leading to increased CYP3A4 and 3A5 activities. 17,18 Clinically, POR*28 may explain a part of calcineurin inhibitors (cyclosporine and Tac) variability, and POR*28 carriers may experience faster Tac metabolism. Indeed, it has been reported that POR*28 carriers have lower residual concentrations (C0) of cyclosporine and lower adjusted Tac C0 (Tac C0/Tac dose) in heart transplantation, 19 and adult 20,21 and pediatric 22 kidney transplantation.…”

Section: Introductionmentioning

confidence: 99%

A Lack of Significant Effect of POR*28 Allelic Variant on Tacrolimus Exposure in Kidney Transplant Recipients

Jannot

Vuillemin

Étienne

et al. 2016

Therapeutic Drug Monitoring

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“…In the general population, the 1508C > T SNP (rs1057868; POR ∗ 28 ) is the most common variant with a reported minor allelic frequency (MAF) of 30% in the white population. POR ∗ 28 encodes the amino acid variant A503V, which has been associated with differential CYP450 activity (de Keyser et al, 2013; Elens et al, 2013d, 2014). For instance, CYP3A5 expressers carrying one or two POR ∗ 28 alleles have shown a 45 % lower midazolam metabolite conversion and higher Tac dose compared with CYP3A5 expressers without POR ∗ 28 (Elens et al, 2013d).…”

Section: Introductionmentioning

confidence: 99%

Tacrolimus Updated Guidelines through popPK Modeling: How to Benefit More from CYP3A Pre-emptive Genotyping Prior to Kidney Transplantation

et al. 2017

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Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD]) profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK) modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window. The objective of the present study was to develop an accurate PopPK model in a cohort of 59 kidney transplant patients to deliver this information to clinicians in a clear and actionable manner. We conducted a non-parametric non-linear effects PopPK modeling analysis in Pmetrics®. Patients were genotyped for the CYP3A4∗22 and CYP3A5∗3 alleles and were classified into 3 different categories [poor-metabolizers (PM), Intermediate-metabolizers (IM) or extensive-metabolizers (EM)]. A one-compartment model with double gamma absorption route described very accurately the tacrolimus PK. In covariate analysis, only CYP3A genotype was retained in the final model (Δ-2LL = -73). Our model estimated that tacrolimus concentrations were 33% IC95%[20–26%], 41% IC95%[36–45%] lower in CYP3A IM and EM when compared to PM, respectively. Virtually, we proved that defining different starting doses for PM, IM and EM would be beneficial by ensuring better probability of target concentrations attainment allowing us to define new dosage recommendations according to patient CYP3A genetic profile.

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Impact of POR*28 on the clinical pharmacokinetics of CYP3A phenotyping probes midazolam and erythromycin

Abstract: Our data show that the POR*28 allele is associated with a lower in vivo CYP3A5 activity, but has no effects on CYP3A4-mediated erythromycin and midazolam metabolism.

Cited by 36 publications

References 37 publications

ABCB1 Polymorphism and Gender Affect the Pharmacokinetics of Amlodipine in Chinese Patients with Essential Hypertension: A Population Analysis

ABCB1 Polymorphism and Gender Affect the Pharmacokinetics of Amlodipine in Chinese Patients with Essential Hypertension: A Population Analysis

A Lack of Significant Effect of POR*28 Allelic Variant on Tacrolimus Exposure in Kidney Transplant Recipients

Tacrolimus Updated Guidelines through popPK Modeling: How to Benefit More from CYP3A Pre-emptive Genotyping Prior to Kidney Transplantation

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