Dihydropyrimidine Dehydrogenase Phenotyping Using Pretreatment Uracil: A Note of Caution Based on a Large Prospective Clinical Study.

In clinical practice, 25-30% of the patients treated with fluoropyrimidines experience severe fluoropyrimidine-related toxicity. Extensively clinically validated DPYD genotyping tests are available to identify patients at risk of severe toxicity due to decreased activity of dihydropyrimidine dehydrogenase (DPD), the rate limiting enzyme in fluoropyrimidine metabolism. In April 2020, the European Medicines Agency recommended that, as an alternative for DPYD genotype-based testing for DPD deficiency, also phenotype testing based on pretreatment plasma uracil levels is a suitable method to identify patients with DPD deficiency.

Comparative evaluation of the left ventricular mass in patients with chronic kidney disease in periodontally healthy, chronic gingivitis, and chronic periodontitis patients.

Objectives: Emerging evidence suggests that inflammation due to periodontal diseases may not be limited to adjacent oral tissues but may have influence on systemic diseases such as chronic kidney diseases (CKD) and cardiovascular diseases. Hence, this study was aimed to evaluate and compare left ventricular mass (LVM) in patients with CKD undergoing hemodialysis (CKDH) in periodontally healthy, chronic gingivitis, and chronic periodontitis.

Methodology: A total of 60Â patients diagnosed with CKDH were divided equally into three groups based on periodontal status as CKDH patients with healthy periodontium (Group I), CKDH patients with chronic gingivitis (Group II), and CKDH patients with chronic periodontitis (Group III).

Point-of-care companion diagnostic tests for personalizing psychiatric medications: fulfilling an unmet clinical need.

Over the last decade stable isotope-labeled substrates have been used as probes for rapid, point-of-care, non-invasive and user-friendly phenotype breath tests to evaluate activity of drug metabolizing enzymes. These diagnostic breath tests can potentially be used as companion diagnostics by physicians to personalize medications, especially psychiatric drugs with narrow therapeutic windows, to monitor the progress of disease severity, medication efficacy and to study in vivo the pharmacokinetics of xenobiotics. Several genotype tests have been approved by the FDA over the last 15 years for both cytochrome P450 2D6 and 2C19 enzymes, however they have not been cleared for use in personalizing medications since they fall woefully short in identifying all non-responders to drugs, especially for the CYP450 enzymes.

The effect of proton pump inhibitors on the CYP2C19 enzyme activity evaluated by the pantoprazole-C breath test in GERD patients: clinical relevance for personalized medicine.

Patients with gastroesophageal reflux disease (GERD) are routinely prescribed one of the six FDA approved proton pump inhibitors (PPI). All of these PPI are inhibitors of CYP2C19 enzyme to varying degrees. The phenotype pantoprazole-C breath test (Ptz-BT) was used to identify patients who are poor metabolizers (PM) and the extent of phenoconversion of CYP2C19 enzyme activity caused by four PPI (omeprazole, esomprazole pantoprazole and rabeprazole) in 54 newly diagnosed GERD patients prior to initiating randomly selected PPI therapy and 30 d after PPI therapy.

Expression of periodontal inflammation into left ventricular hypertrophy in Type 2 diabetes mellitus: A cross-sectional study.

Background: Chronic periodontitis, an inflammatory disease, is closely related to certain systemic conditions such as cardiovascular diseases, obesity, and Type 2 diabetes mellitus. These conditions, occurring as comorbidities, synergically affect periodontal tissues.

Aim: This study aims to examine whether chronic gingivitis and chronic generalized severe periodontitis in patients with Type 2 diabetes mellitus are associated with increased left ventricular mass (LVM).

Changes in CYP2C19 enzyme activity evaluated by the [(13)C]-pantoprazole breath test after co-administration of clopidogrel and proton pump inhibitors following percutaneous coronary intervention and correlation to platelet reactivity.

Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is used for the prevention of cardiovascular events following percutaneous coronary intervention (PCI). These agents increase the risk of gastrointestinal bleeding. To prevent these events, proton pump inhibitors (PPI) are routinely prescribed.

CYP2C19 Phenoconversion by Routinely Prescribed Proton Pump Inhibitors Omeprazole and Esomeprazole: Clinical Implications for Personalized Medicine.

The phenotype pantoprazole-(13)C breath test (Ptz-BT) was used to evaluate the extent of phenoconversion of CYP2C19 enzyme activity caused by commonly prescribed proton pump inhibitors (PPI) omeprazole and esomprazole. The Ptz-BT was administered to 26 healthy volunteers and 8 stable cardiovascular patients twice at baseline and after 28 days of PPI therapy to evaluate reproducibility of the Ptz-BT and changes in CYP2C19 enzyme activity (phenoconversion) after PPI therapy. The average intrapatient interday variability in CYP2C19 phenotype (n = 31) determined by Ptz-BT was considerably low (coefficient of variation, 17%).

Evaluation of CYP2D6 enzyme activity using a 13C-dextromethorphan breath test in women receiving adjuvant tamoxifen.

Background: In tamoxifen-treated patients, breast cancer recurrence differs according to CYP2D6 genotype and endoxifen steady-state concentrations (Endx Css). The ¹³C-dextromethorphan breath test (DM-BT), labeled with ¹³C at the O-CH3 moiety, measures CYP2D6 enzyme activity. We sought to examine the ability of the DM-BT to identify known CYP2D6 genotypic poor metabolizers and examine the correlation between DM-BT and Endx Css.

Breath tests to phenotype drug disposition in oncology.

Breath tests (BTs) have been investigated as diagnostic tools to phenotype drug disposition in cancer patients in the pursuit to individualize drug treatment. The choice of the right phenotype probe is crucial and depends on the metabolic pathway of the anticancer agent of interest. BTs using orally or intravenously administered selective non-radioactive (13)C-labeled probes to non-invasively evaluate dihydropyrimidine dehydrogenase, cytochrome P450 (CYP) 3A4, and CYP2D6 enzyme activity have been published.

Regulatory issues on breath tests and updates of recent advances on [13C]-breath tests.

Over the last decade non invasive diagnostic phenotype [(13)C]-breath tests as well as tests using endogenous volatile organic compounds (VOCs) in breath have been researched extensively. However, only three breath tests have been approved by the FDA over the last 15 years. Despite the potential benefits of these companion diagnostic tests (CDx) for evaluation of drug metabolizing enzyme activities and standalone diagnostic tests for disease diagnosis to personalize medicine, the clinical and commercial development of breath tests will need to overcome a number of regulatory, financial and scientific hurdles prior to their acceptance into routine clinical practice.

Is (+)-[13C]-pantoprazole better than (±)-[13C]-pantoprazole for the breath test to evaluate CYP2C19 enzyme activity?

Recently, we have shown that the (+)-[(13)C]-pantoprazole is more dependent on CYP2C19 metabolic status than (-)-[(13)C]-pantoprazole. In this study, we tested the hypothesis that (+)-[(13)C]-pantoprazole is a more sensitive and selective probe for evaluating CYP2C19 enzyme activity than the racemic mixture. (+)-[(13)C]-pantoprazole (95 mg) was administered orally in a sodium bicarbonate solution to healthy volunteers.

A rapid non invasive L-DOPA-¹³C breath test for optimally suppressing extracerebral AADC enzyme activity - toward individualizing carbidopa therapy in Parkinson’s disease.

Background: Peripheral carbidopa (CD) levels directly impact on central dopamine (DA) production in Parkinson disease (PD) through extracerebral inhibition of dopa decarboxylase (AADC) resulting in an increase in levodopa (LD) bioavailability.

Objective: Recent data suggests that higher CD doses than those presently used in PD treatment may result in improved clinical response. Optimizing CD doses in individual patients may, therefore, result in ideal individualized treatment.

Stereoselective pharmacokinetics of stable isotope (+/-)-[13C]-pantoprazole: Implications for a rapid screening phenotype test of CYP2C19 activity.

Aims: We have previously shown that the (±)-[(13) C]-pantoprazole breath test is a promising noninvasive probe of CYP2C19 activity. As part of that trial, plasma, breath test indices and CYP2C19 (*2, *3, and *17) genotype were collected. Here, we examined whether [(13) C]-pantoprazole exhibits enantioselective pharmacokinetics and whether this enantioselectivity is correlated with indices of breath test.

Breath biomarkers for personalized medicine.

Personalized medicine, in the near future, has the potential to revolutionize healthcare by allowing physicians to individualize therapy for patients through the early diagnosis of disease and risk assessment to optimize clinical response with minimal toxicity. The identification of biomarkers could detect, diagnose and help guide therapy to improve survival and quality of life by the early identification of responders to the drugs. Volatile organic compounds and stable isotope-labeled CO in breath can be uniquely utilized as in vivo diagnostic biomarkers of disease and/or lack of enzyme activity to aid physicians to personalize medication.

Single time point diagnostic breath tests: a review.

The metabolism of ingested xenobiotics is clinically significant to minimize risk and optimize therapeutic benefits. A majority of the drugs approved by the FDA are metabolized by phase I enzymes. Stable isotope-labeled xenobiotics can be used to provide rapid in vivo phenotype assessment of phase I enzymes.

(13)C-5-FU breath test current status and future directions: a comprehensive review.

Breath tests (BTs) represent a safe non-invasive alternative strategy that could provide valuable diagnostic information in conditions like fat malabsorption, carbohydrate (lactose and fructose) malabsorption, liver dysfunction, impaired gastric emptying, abnormal small bowel transit time, small intestinal bacterial overgrowth and Helicobacter pylori infection. To date, despite the availability of a number of breath tests, only three have gained approval by the FDA for application in a clinical setting ((13)C-urea breath test for the detection of H. pylori; NO breath test for monitoring asthma and alkane breath test for heart transplant rejection).

Breath tests with (13)C substrates.

Labeled (stable and radio) isotope compounds ((2)H, (3)H, (14)C, (13)C, (15)N) have been widely used as diagnostic probes in research laboratories for over 30 years in the fields of gastroenterology, hepatology, oncology, and nutrition, as well as pharmacokinetic studies in the development of drugs. (13)C stable isotope diagnostic probes are now being expanded in their scope, to provide precise evaluations of the presence or absence of etiologically significant changes in metabolism due to a specific disease or the lack of a specific enzyme. The concept exploits the use of the (13)C- label that is incorporated at the appropriate site into a selected substrate specifically designed for the targeted enzyme in a discrete metabolic pathway.

(13)C breath tests in personalized medicine: fiction or reality?

The concept of personalized medicine is gathering momentum as various biomarkers are being discovered and developed to lead to genotype and phenotype diagnostic tests, which will enable physicians to individualize therapy. Noninvasive, rapid (13)C breath tests have the potential to serve as clinically significant diagnostic tools, especially for evaluating the enzyme activity of polymorphic enzymes. This would enable physicians to rapidly identify responders/nonresponders to various drugs primarily metabolized by these enzymes prior to initiation of therapy.

Rapid identification of the hepatic cytochrome P450 2C19 activity using a novel and noninvasive [13C]pantoprazole breath test.

We tested the hypothesis that the stable isotope [(13)C]pantoprazole is O-demethylated by cytochrome P450 CYP2C19 and that the (13)CO(2) produced and exhaled in breath as a result can serve as a safe, rapid, and noninvasive phenotyping marker of CYP2C19 activity in vivo. Healthy volunteers who had been genotyped for the CYP2C19(*)2, CYP2C19(*)3, and CYP2C19(*)17 alleles were administered a single oral dose of [(13)C]pantoprazole sodium-sesquihydrate (100 mg) with 2.1 g of sodium bicarbonate.

Evaluation of a [13C]-dextromethorphan breath test to assess CYP2D6 phenotype.

A [(13)C]-dextromethorphan ([(13)C]-DM) breath test was evaluated to assess its feasibility as a rapid, phenotyping assay for CYP2D6 activity. [(13)C]-DM (0.5 mg/kg) was administered orally with water or potassium bicarbonate-sodium bicarbonate to 30 adult Caucasian volunteers (n=1 each): CYP2D6 poor metabolizers (2 null alleles; PM-0) and extensive metabolizers with 1 (EM-1) or 2 functional alleles (EM-2).

L-[1-(13)C] phenylalanine breath test for monitoring hepatic function after living donor liver transplant surgery.

Although metabolic response after partial hepatectomy has been well studied in animal models, there are few studies examining restoration of metabolic capacity after right hepatectomy in humans. The L-[1-(13)C]-phenylalanine breath test (PBT) is a simple non-invasive diagnostic tool which allows measurement of liver functional reserve. We investigated the PBT for monitoring hepatic function in living liver donors by measuring the metabolism of L-[1-(13)C]-phenylalanine ((13)C-Phe).

Stable isotope breath tests in clinical medicine: a review.

Diagnostic (13)C-stable isotope probes are currently being expanded in their scope, to provide precise evaluations of the presence or absence of etiologically significant changes in metabolism due to a specific disease or the lack of a specific enzyme. The salient features of the (13)C-breath test are that they are non-invasive, non-radioactive, safe, simple, and effective. The simplicity of the (13)C-breath test makes it very applicable in a clinical setting: the physician can obtain valuable diagnostic information by distinguishing between two groups or populations on the basis of the recovery of (13)CO(2) from the ingested (13)C-substrate.