Aze Wilson

Trimethylamine-N-oxide: a link between the gut microbiome, bile acid metabolism, and atherosclerosis.

Purpose of review This article evaluates the link between trimethylamine-N-oxide (TMAO) and bile acids and the consequent impact on the development of atherosclerosis. Recent findings Elevation in plasma TMAO concentrations is associated with an increased risk of cardiovascular disease in many different patient cohorts. In addition to the recently identified direct effects of TMAO on the development of atherosclerosis, other components involved in TMAO metabolism may also have an impact. Furthermore, the relationship between TMAO and bile acid regulation is emerging as a possible mediator of atherosclerosis. Summary Studies that are emerging highlight the mechanistic relationship of TMAO to the development atherosclerosis in addition to its role as disease biomarker. The interplay between TMAO and bile acid metabolism mediated through multiple factors, such as the gut microbiome, farnesoid X receptor signaling, and flavin monooxygenase 3 activity may help identify another pathway by which atherosclerosis occurs. In this review, we discuss the most recent data regarding atherosclerosis, TMAO, and bile acid metabolism.

Pharmacokinetic profiles for oral and subcutaneous methotrexate in patients with Crohn's disease.

Methotrexate (MTX) is administered subcutaneously to Crohns Disease (CD) patients. There are very few studies evaluating the use of oral (PO) MTX in CD. A drug and its pharmaceutical alternative are equivalent (bioequivalence) when the bioavailability of the alternative falls within 80–125% of the bioavailability of the standard (US Food and Drug Administration ‐ FDA).

Identification and Characterization of Trimethylamine-N-oxide Uptake and Efflux Transporters

Trimethylamine-N-oxide (TMAO) is a recently identified predictor of cardiovascular and chronic kidney disease. TMAO is primarily generated through gut-microbiome mediated conversion of dietary choline and carnitine to TMA, which is converted to TMAO by hepatic flavin monooxygenase 3 (FMO3) and subsequently undergoes renal elimination. We investigated the role of uptake and efflux drug transporters in TMAO disposition in vitro and in vivo. After screening a large array of uptake transporters, we show organic cation transporter 2 (OCT2) is the key transporter for TMAO cellular uptake. In Oct1/2 knockout mice, we observed increased plasma TMAO levels with reduced renal retention, suggesting the importance of Oct2 in facilitating the uptake of TMAO into renal tubular cells in vivo. Multiple transporters of the ATP-binding cassette (ABC) family, including ABCG2 (BCRP) and ABCB1 (MDR1), were capable of TMAO efflux. In human subjects, clinical, dietary, and pharmacogenetic covariates were evaluated for contribution to TMAO levels in a cohort of dyslipidemic patients (n = 405). Interestingly, genetic variation in ABCG2, but not other transporters, appeared to play a role in modulating TMAO exposure.

Impact of Transporter Polymorphisms on Drug Development: Is It Clinically Significant?

Drug transporters are becoming increasingly recognized as relevant to the drug development process. This may be a reflection of increasing target complexity and the need for high‐affinity interaction with drug targets that minimize off‐target side effects. Moreover, as new molecular entities (NMEs) become larger in size and amphipathic in nature, interaction with drug transporters, both uptake as well as efflux, becomes increasingly likely. In some cases transporters may limit the absorption or organ‐specific entry of NMEs, whereas in other cases transporters may enhance their absorption or tissue accumulation. Indeed, in some cases, transporters may prove to be a therapeutic target. Accordingly, a better understanding of potentially clinically relevant drug transporter polymorphisms earlier in the drug development process is highly desirable. In this review we examine key transporters that are important to the absorption, distribution, and excretion of a large number of drugs in clinical use. Importantly, we provide our assessment of the potential impact of known polymorphisms in such transporters and discuss whether there is sufficient evidence to incorporate these polymorphisms in the drug development process.

Candida glabrata Esophagitis: Are We Seeing the Emergence of a New Azole-Resistant Pathogen?

Background. Candida glabrata (C. glabrata) has become a recognized pathogen in fungal esophagitis. A proportion of these isolates are azole-resistant which may have treatment implications. Variability in the prevalence of this organism exists in the limited data available. Objective. To determine the incidence of C. glabrata esophagitis in a North American hospital setting and to highlight factors that may predispose patients to this condition. Methods. Patient charts were collected from January 1, 2009 to July 30, 2011. Any charts of patients identified as having esophagitis with a positive fungal culture were reviewed for the species of Candida and the presence of factors that would predispose them to esophageal candidiasis. Results. The prevalence of Candida esophagitis based on culture was 2.2% (37 subjects). C. glabrata was the 2nd most prevalent pathogen identified (24.3% or 9 subjects). Of the C. glabrata cohort, all patients had at least one factor predisposing them to candidiasis. Conclusion. C. glabrata esophagitis makes up a large portion of the candidal esophagitis seen in hospital. C. glabrata infections were associated with at least one risk factor for candidal infection. Given its resistance to azole-based therapy, this may have treatment implications for how candidal esophagitis is approached by the clinician.

HLA-DQA1-HLA-DRB1 polymorphism is a major predictor of azathioprine-induced pancreatitis in patients with inflammatory bowel disease

Azathioprine (AZA)‐induced pancreatitis is an unpredictable and dose‐independent adverse event affecting 2%‐7% of patients with inflammatory bowel disease (IBD) patients treated with AZA. There are no tools in clinical practice to identify at‐risk individuals; however, a genome wide association study (GWAS) identified a strong association between the Class II HLA gene region polymorphism (rs2647087) and thiopurine‐induced pancreatitis.

Letter: predicting azathioprine-associated pancreatitis in IBD-phenotype or genotype? Authors' reply

EDITORS, We thank Teich et al for their comments and recognise there are differences in opinion with regards to the treatment algorithm as outlined in our study. There are undoubtedly other risk factors associated with the onset of azathioprine (AZA)-induced pancreatitis, even beyond those identified by Teich et al in their own work. Our algorithm was based on new insights regarding genetic determinants of variation in drug response as a way to guide clinicians on how to incorporate a novel genomic marker in clinical practice to enhance the safe use of AZA. In terms of cost-effectiveness, we note that genotype-guided dosing of AZA using TPMT genotypes has been shown to be more cost-effective than standard practice in several studies. Thompson et al (2014) published an economic evaluation of the TARGET Study (2011). This group showed that TPMT genotyping resulted in lower costs compared to the standard practice of step-wise dose escalation with monitoring of biochemical and haematological parameters. This confirmed work by Payne et al (2009) in an analysis of 6 retrospective economic evaluations of TPMT-guided AZA dosing, all of which emphasised its cost-effectiveness compared to standard practice. While the allele frequency of the rs2647087 variant genotype is relatively high, it is debatable whether or not AZA should be withheld from this population. The genomic data allow physicians to enter into a more informed discussion with their patient regarding the risks associated with AZA, whether used as monotherapy or in combination with a biologic, as well as discussion on other steroidsparing alternatives such as methotrexate. In our cohort of patients, AZA-induced pancreatitis resulted in hospitalisation for all patients. Thus, while not severe, affected patients were of sufficient concern to warrant hospitalisation. Lastly, Teich et al suggest that genomic-based dosing strategies for AZA are not effective, citing Coenen et al (2015). The utility of pre-emptive TPMT genotyping is widely accepted. Canadian, American and British Gastroenterology Society guidelines, all advocate for pre-emptive TPMT genotyping prior to the introduction of thiopurine-based therapies in IBD. The evidence for TPMTguided dosing comes from robust mechanistic studies in addition to retrospective analyses supporting dose reduction in TPMT variant carriers summarised in the Clinical Pharmacogenetics Implementation Consortium Guideline. Randomised control studies such as the Coenen et al (2015) study are insufficiently powered to show the benefit of TPMT-guided AZA dosing in general populations due to the rarity of variant TPMT genotypes. The greatest benefit is seen at the level of the variant carriers as was demonstrated by Coenen et al (2015). A 10-fold reduction in haematologic adverse drug reactions was seen in the variant TPMT carriers in the intervention group (2.9%) versus the control group (22.9%) with a number needed to treat of five for patients carrying a TPMT risk allele. Ultimately, genotype-guided dosing algorithms for AZA have a role in IBD management particularly given the number of alternative therapeutic agents available, as well as the continued reduction in cost of genotype testing to enhance efficacy and reduce harm from AZA therapy.