Statins
The statin drug class is known to inhibit the cholesterol-synthesizing enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is present in humans and in certain bacterial organisms, such as Enterococcus faecalis and Enterococcus faecium. The interactions between statins, bile acid metabolism, cholesterol synthesis, and the gut microbiome are quite complex; therefore, they have been the target of many recent studies. Importantly, certain species of gut microbiota (including well-studied probiotic strains such as Lactobacillus and Bifidobacterium) are vital sources of a group of enzymes known as bile salt hydrolases (BSHs).[12] Bile salts are synthesized from cholesterol by the liver and then metabolized by the gut microbiome into a variety of bile salt derivatives, which are then reabsorbed and further metabolized by the liver, giving rise to a large, diverse pool of complex bile salts that aid in digestion and may protect against harmful organisms such as Clostridium difficile.[12] Because LDL-cholesterol concentrations are inversely correlated with circulating bile acids, it has been hypothesized that the cholesterol-lowering effect of statins may be linked to the activity of bacteria-containing BSHs such as Lactobacillus. In a randomized, placebo-controlled clinical trial involving 127 participants, treatment with the probiotic Lactobacillus reuteri was shown to significantly reduce LDL-cholesterol concentrations.[13]
Uniquely among the statins, lovastatin is a prodrug that must be metabolized by the gut microbiome from a gamma-lactone closed ring to the beta hydroxy acid open-ring form in order to be active.[7] Yoo and colleagues investigated impairment of lovastatin bioactivation by the gut microbiome in antibiotic-treated rats given several different antibiotics, including ampicillin and a broad-spectrum antibiotic mixture consisting of cefadroxil, oxytetracycline, and erythromycin.[7] The concentration of the active metabolite of lovastatin was approximately 60% lower in antibiotic-treated rats than in control rats, which were not given antibiotics.[7] These results suggest that antibiotics may reduce the effectiveness of lovastatin by disrupting the gut microbiome's bioactivation of the prodrug.
Consideration of how the microbiome directly influences lovastatin pharmacokinetics and how the statin class decreases the amount of specific bacterial species and therefore modulates the enzymes involved in bile acid metabolism makes it apparent that the most common cholesterol-lowering drugs are also impacting patients' critical gut microbiota and their cardiovascular health.[7,13] Exploration of the complex relationships existing between the gut microbiome and cardiovascular drugs, including cholesterol-lowering therapies, should continue.
US Pharmacist. 2023;48(2):18-22. © 2023 Jobson Publishing
