Metabolism of alprazolam (a marker of CYP3A4) in hemodialysis patients with persistent inflammation

Molanaei, Hadi; Stenvinkel, Peter; Qureshi, Abdul Rashid; Carrero, Juan Jesús; Heimbürger, Olof; Lindholm, Bengt; Diczfalusy, Ulf; Odar‐Cederlöf, Ingegerd

doi:10.1007/s00228-011-1163-8

Cited by 24 publications

(31 citation statements)

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“…In a small (n = 26) recent study in patients with end-stage renal disease, an association between inflammation (increased CRP) and low CYP3A4 activity assessed by alprazolam 4-hydroxylation was noted, but there was no correlation between inflammation and 4b-hydroxycholesterol (Molanaei et al, 2012). Alprazolam 4-hydroxylation is a marker for rapid changes in CYP3A4 activity, whereas 4b-hydroxycholesterol reflects CYP3A4 activity over longer time periods and is more useful in determining induction than inhibition of CYP3A4.…”

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confidence: 91%

“…Furthermore, this study material included patients with high frequency of infections, offering an opportunity to study whether acute inflammation, measured as C-reactive protein (CRP), impacts on the CYP3A biomarker. It was previously shown in cell and animal experiments that infections and inflammation can downregulate CYP3A4 expression (Morgan et al, 2008;Morgan, 2009), and a recent study in hemodialysis patients indicated a correlation between CYP3A4-dependent alprazolam 4-hydroxylation and CRP (Molanaei et al, 2012).…”

Section: Introductionmentioning

confidence: 95%

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Serum Levels of 25-Hydroxyvitamin D and the CYP3A Biomarker 4β-Hydroxycholesterol in a High-Dose Vitamin D Supplementation Study

et al. 2013

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The primary aim was to study the relationship between individual serum levels of 25-hydroxyvitamin D and 4b-hydroxycholesterol, which is an endogenous biomarker of the drug-metabolizing CYP3A enzymes. In addition, the relationship between this biomarker and inflammation, measured as C-reactive protein (CRP), was investigated. Serum samples were used from a recently performed clinical trial in patients with antibody deficiency or increased susceptibility to respiratory tract infections that were randomized to either placebo or high-dose (4000 IU/day) vitamin D for 12 months. One hundred sixteen patients were included in the final analyses, and serum samples collected 6 months after study start were analyzed. At this time point, 25-hydroxyvitamin D levels were found to range between 10 and 284 nM. Individual levels of 25-hydroxyvitamin D as well as CRP were compared with 4b-hydroxycholesterol levels. In addition, all participants were genotyped for two polymorphisms (Taq1 and Foq1) in the vitamin D receptor gene. There was no significant correlation between individual serum levels of 25-hydroxyvitamin D and 4b-hydroxycholesterol. However, a moderate, but statistically significant, negative correlation between CRP and 4b-hydroxycholesterol levels was observed. This study in patients with highly variable serum levels of 25-hydroxyvitamin D could not reveal any relationship between vitamin D and 4b-hydroxycholesterol, an endogenous biomarker of CYP3A activity. However, the negative correlation between CRP and 4b-hydroxycholesterol supports earlier experimental results that inflammation may suppress hepatic CYP3A activity, a finding of potentially high clinical relevance that warrants further exploration.

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confidence: 91%

Section: Introductionmentioning

confidence: 95%

Serum Levels of 25-Hydroxyvitamin D and the CYP3A Biomarker 4β-Hydroxycholesterol in a High-Dose Vitamin D Supplementation Study

et al. 2013

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“…In addition, in CKD patients, mitigation of CYPmediated drug metabolism is shown, 113,114 including changes in bupropion, alprazolam, and fexofenadine pharmacokinetics. [115][116][117] Moreover, is has been shown both in vitro and in vivo that hemodialysis improves functional expression of hepatic CYP3A4, 118,119 implicating a role for uremic toxins in altering drug metabolism in CKD patients. This notion is supported by the study from Sun et al, 120 which showed that indoxyl sulfate and CMPF reduced erythromycin metabolism by CYP3A in rat liver microsomes.…”

Section: Intracellular Fate Of Uremic Toxinsmentioning

confidence: 99%

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Masereeuw

Mutsaers

Toyohara³

et al. 2014

Seminars in Nephrology

134

122

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This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited.

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“…A study on the effect of persistent inflammation in patients with renal failure and who were undergoing hemodialysis on the pharmacokinetics of alprazolam, a CYP3A4 substrate, revealed that after a single dose of alprazolam, there was a significant correlation between CYP3A4 activity and CRP level, which suggested that inflammation may clinically down-regulate CYP3A4 activity (Molanaei et al, 2012). Studies in human liver microsomes have shown that oxatomide, an H1-antihistamine, is mainly metabolized by CYP3A4 and CYP2D6, and there has been a report of severe long-lasting impaired consciousness induced by therapeutic doses of oxatomide in a child affected by acute gastroenteritis (Antoniazzi et al, 2012).…”

Section: Evidence For Potential Phenoconversion Of Dmes In Other Inflmentioning

confidence: 99%

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

Shah¹,

2014

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Phenoconversion transiently converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, potentially with corresponding changes in clinical response. This phenomenon, typically resulting from coadministration of medications that inhibit certain drug metabolizing enzymes (DMEs), is especially well documented for enzymes of the cytochrome P450 family. Nonclinical evidence gathered over the last two decades also strongly implicates elevated levels of some proinflammatory cytokines, released during inflammation, in down-regulation of drug metabolism, especially by certain DMEs of the P450 family, thereby potentially causing transient phenoconversion. Clinically, phenoconversion of NAT2, CYP2C19, and CYP2D6 has been documented in inflammatory conditions associated with elevated cytokines, such as human immunodeficiency virus infection, cancer, and liver disease. The potential of other inflammatory conditions to cause phenoconversion has not been studied but experimental and anecdotal clinical evidence supports infectioninduced down-regulation of CYP1A2, CYP3A4, and CYP2C9 as well. Collectively, the evidence supports a hypothesis that certain inflammatory conditions associated with elevated proinflammatory cytokines may cause phenoconversion of certain DMEs. Since inflammatory conditions associated with elevated levels of proinflammatory cytokines are highly prevalent, phenoconversion of genotypic EM patients into transient phenotypic PMs may be more frequent than appreciated. Since drug pharmacokinetics, and therefore the clinical response, is influenced by DME phenotype rather than genotype per se, phenoconversion (whatever its cause) can have a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies. There is a risk that focusing on genotype alone may miss important associations between clinical outcomes and DME phenotypes, thus compromising future prospects of personalized medicine.

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Metabolism of alprazolam (a marker of CYP3A4) in hemodialysis patients with persistent inflammation

Abstract: The correlation between CYP3A4 activity (assessed by alprazolam 4-hydroxylation) and CRP level suggests that inflammation may downregulate CYP3A4 activity. If confirmed, this could have major implications for drug dosing in persistently inflamed patients.

Cited by 24 publications

References 31 publications

Serum Levels of 25-Hydroxyvitamin D and the CYP3A Biomarker 4β-Hydroxycholesterol in a High-Dose Vitamin D Supplementation Study

Serum Levels of 25-Hydroxyvitamin D and the CYP3A Biomarker 4β-Hydroxycholesterol in a High-Dose Vitamin D Supplementation Study

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

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