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hERG channel inhibition & cardiotoxicity

directory of Chem Help ASAP videos: https://www.chemhelpasap.com/youtube/ The hERG story starts with terfenadine. Terfenadine was a drug that reached the market in the middle 1980s. Terfenadine itself is inactive, but undergoes rapid metabolism in the body, specifically by the 3A4 isoform of cytochrome P-450, to form an active metabolite, fexofenadine. Therefore, the terfenadine is an example of a prodrug, and its circulating plasma levels are quite low because of rapid metabolism. The activity of terfenadine as an antihistamine for allergy symptoms is from the metabolite. Unfortunately, terfenadine had a very serious, unidentified safety risk. In certain situations, CYP3A4 metabolism can be inhibited. For example, certain foods can inhibit drug metabolism. Sometimes other drugs can inhibit drug metabolism. If a patient on terfenadine experiences reduced CYP3A4 metabolism, then the plasma levels of terfenadine will rise beyond their expected values. There are two consequences. One, the amount of fexofenadine will be reduced, and the patient may not experience the therapeutic benefit from taking terfenadine as a drug. That is indeed unfortunate, but the more serious consequence is that terfenadine is cardiotoxic. In fact, elevated terfenadine levels can lead to patient death, and a small number of deaths were reported soon after terfenadine was approved. By 1990, terfenadine was withdrawn from the market. The risks of terfenadine slipped through preclinical safety because this exact situation had not been recognized as a safety concern. What exactly is the safety risk and origin of terfenadine’s toxicity? The risks involve hERG. hERG stands for human ether-a-go-go-related gene, and hERG encodes a protein, Kv11.1, that is part of a critical potassium ion channel in the heart. While arguably inaccurate, people often call the ion channel protein hERG, though hERG is technically the gene that encodes the protein. Regardless, inhibition of this ion channel affects the proper function of the heart and therefore can lead to patient death. This was the problem with terfenadine. Terfenadine built up in the plasma because of reduced metabolism and inhibited hERG ion channel activity. Because of the safety risks of terfenadine, drug discovery teams have become more aware of potential hERG inhibition. Monitoring hERG binding has now become a standard part of every new drug program and technically falls under the umbrella of safety pharmacology. If you read a literature article about a drug discovery program, you are very likely to find some comments about the hERG activity of compounds studied. There are multiple in vitro assays that can detect and quantify hERG channel inhibition or binding. There is no strict cutoff for safety levels of binding or inhibition, but many programs strive for advanced compounds to have an IC50 on hERG that is greater than or equal to 30-to-50-times the therapeutic unbound plasma concentration.