Pharmacogenomics of Cytochrome P450 3A4: Recent Progress Toward the “Missing Heritability” Problem.

Pharmacogenomics of Cytochrome P450 3A4: Recent Progress Toward the “Missing Heritability” Problem.

Front Genet. 2013; 4: 12
Klein K, Zanger UM

CYP3A4 is the most important drug metabolizing enzyme in adult humans because of its prominent expression in liver and gut and because of its broad substrate specificity, which includes drugs from most therapeutic categories and many endogenous substances. Expression and function of CYP3A4 vary extensively both intra- and interindividually thus contributing to unpredictable drug response and toxicity. A multitude of environmental, genetic, and physiological factors are known to influence CYP3A4 expression and activity. Among the best predictable sources of variation are drug-drug interactions, which are either caused by pregnane X-receptor (PXR), constitutive androstane receptor (CAR) mediated gene induction, or by inhibition through coadministered drugs or other chemicals, including also plant and food ingredients. Among physiological and pathophysiological factors are hormonal status, age, and gender, the latter of which was shown to result in higher levels in females compared to males, as well as inflammatory processes that downregulate CYP3A4 transcription. Despite the influence of these non-genetic factors, the genetic influence on CYP3A4 activity was estimated in previous twin studies and using information on repeated drug administration to account for 66% up to 88% of the interindividual variation. Although many single nucleotide polymorphisms (SNPs) within the CYP3A locus have been identified, genetic association studies have so far failed to explain a major part of the phenotypic variability. The term “missing heritability” has been used to denominate the gap between expected and known genetic contribution, e.g., for complex diseases, and is also used here in analogy. In this review we summarize CYP3A4 pharmacogenetics/genomics from the early inheritance estimations up to the most recent genetic and clinical studies, including new findings about SNPs in CYP3A4 (*22) and other genes (P450 oxidoreductase (POR), peroxisome proliferator-activated receptor alpha (PPARA)) with possible contribution to CYP3A4 variable expression. HubMed – drug

Cost Effectiveness of Antiarrhythmic Medications in Patients Suffering from Atrial Fibrillation.

Pharmacoeconomics. 2013 Feb 27;
Brüggenjürgen B, Kohler S, Ezzat N, Reinhold T, Willich SN

Atrial fibrillation (AF), a supraventricular tachycardia disorder, is the most common sustained cardiac arrhythmia affecting 1-2 % of the general population. Prevalence is highly related to age, with every fourth individual older than 40 years old developing AF during his lifetime. Due to an aging population, the prevalence of AF is estimated to at least double within the next 50 years. This article presents AF-related cost-of-illness studies and reviews 19 cost-effectiveness studies and six cost studies published roughly over the past decade, which have compared different antiarrhythmic medications for AF. A systematic literature search for studies published between June 2000 and December 2011 was conducted in PubMed using the combination of keywords ((atrial fibrillation OR atrial flutter) AND cost). Current cost-effectiveness analyses of dronedarone and the pill-in-the-pocket strategy are subject to substantial uncertainties with regard to clinical benefit. Comparing rate control with rhythm control, a cost-effectiveness advantage for rate control was shown in several but not all studies. Within antiarrhythmic drug treatments, magnesium added onto ibutilide was shown to be more cost effective than ibutilide alone. Comparing chemical and electrical cardioversion, the latter was recommended as more cost effective from the healthcare system perspective in all reviewed studies but one. Catheter ablation appeared more cost effective than antiarrhythmic drugs in the medium to long run after 3.2-63.9 years. Admissions to hospital, inpatient care and interventional procedures as well as mortality benefit are key drivers for the cost effectiveness of AF medications. No clear cost-effectiveness advantage emerged for one specific antiarrhythmic drug from the studies that compared antiarrhythmic agents. Rate control as well as catheter ablation appear more cost effective than rhythm control in the treatment of AF. Rate control treatment also seems more cost effective than electrical cardioversion in AF patients. HubMed – drug

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