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Drug metabolizing enzymes in cancer therapeutics
Published on June 28, 2018 26 min
Other Talks in the Series: Cancer Therapies in the Personalized Medicine Era
Hello. My name is Bhagwat Prasad and I'm an assistant professor at the Department of Pharmaceutics, University of Washington, Seattle WA, USA. I'm going to talk today about drug metabolizing enzymes and cancer therapeutics.
So, content of my slides include the definition of drug metabolism; classification of drug-metabolizing enzymes, commonly referred as DMEs; and clinical significance of DMEs in cancer therapeutics. I will be mainly focusing on three parts. First is on drug delivery to cancer cells, and drug resistance, and interindividual variability and leveraging interindividual variabilty in precision oncology.
Drug metabolism is a part of pharmacology in a broader sense. If we think about pharmacology, pharmacology is divided into two parts; pharmacokinetics and pharmacodynamics. Pharmacokinetics is described as what body does to the drugs, while pharmacodynamics is what drug does to the body. In phamacokinetics, mechanistically, we can define pharmacokinetics as drug distribution. So, when your drug is taken, it's absorbed, it's distributed in the body, and it's eliminated by two processes. One is excretion from body as such, or by chemical biotransmission of drugs called drug metabolism. So, drug metabolism can be classified further into two categories, Phase I drug metabolism and Phase II drug metabolism. In Phase I drug metabolism, a drug which is usually lipophilic is converted to a slightly water-soluble molecule by oxidation or hydrolysis or reduction of processes and that the hydrolyzed or reduced or oxidized moiety is further conjugated with endogenous molecules like gluconic acid in Phase II in drug metabolism step which gives you a very hydrophilic metabolite that can be eliminated by a simple excretion from body. The primary sites of drug metabolism are liver, intestine, and kidney. For this talk, in case of cancer cells, the cancer cells overexpresses these drug-metabolizing enzymes so they become as a site of drug metabolism as well. There is further complexity in drug metabolism because most of the drugs that are being developed are substrates of drug transporters. This is called Phase 0 drug metabolism in this case, or drug distribution where drug is taken up by active transporters or some kind of protein couriers that takes drugs from the blood to a cell for example, cancer cell. Then also, these hydrophilic moieties are excreted through the transport processes.