Skip to 0 minutes and 2 secondsWelcome to the session on genetics and pharmacokinetics. In this session, we will look at how genetic variation affects the body in the way that it handles drugs. To start with, we will discuss how drugs are administered into the body and we will think about how drug concentrations can vary amongst different individuals. We will also focus on how genetic variation can affect three key areas, namely the absorption of the drug, the metabolism of the drug, and the excretion of the drug. The importance of pharmacokinetics stems from the fact that drugs have to be administered in an acceptable and feasible way, and this may include oral tablets, injections, active preparations ,and topical products such as skin creams and eye drops.
Skip to 1 minute and 1 secondOnce the drug has been administered, the substance has to traverse the body and the active compound has to reach the target site within the body, and hopefully the active compound will remain at the target for a sufficiently long duration that a beneficial effect results for the patient. Ideally, the drug will be at an appropriate concentration in the body and it would subsequently be eliminated from the body in a consistent and predictable way. Obviously, we would like to target a drug concentration that delivers good beneficial effects but equally, at a level where adverse reactions are unlikely to take place. Now, genetic variations can affect pharmacokinetics through a number of ways.
Skip to 2 minutes and 6 secondsFirstly, the drug concentration can be affected because of genetic variation in bioavailability, namely, how well it might be absorbed from the stomach, for example. Some drugs require transporters to bring the drug into the body through the intestinal cells and there may be variation in how well these transporters bring the drug in, depending on the genetic makeup of the individual. Now as the drug enters the body - something known as first pass metabolism can take place. This may have activation or breakdown of the drug. Genetic variation can affect the activity of enzymes that process these drugs as the drug travels into the body. Now once the drug is in the body, it will eventually have to be broken down and moved.
Skip to 3 minutes and 2 secondsThis may be a metabolic process or may be excreted through the renal system. Again, genetic variation can affect the activity of these transporters and the enzymes that are involved in eliminating the drug. Let's look at an example of variation in drug absorption. Now we take as an example here methotrexate. There's considerable variation in methotrexate dosing and this stems partly from differences in absorption from the gastrointestinal tract.
Skip to 3 minutes and 42 secondsThere are membrane transport proteins that have different affinity for methotrexate. Equally, the oral bioavailability is also affected by the ABC transporters that push the methotrexate back out into the intestinal lumen, where it is lost.
Skip to 4 minutes and 6 secondsNow variation in metabolism is a very important part of pharmacokinetics. Our example here is a drug known as codeine which is a very widely used painkiller. Codeine is metabolised in the liver by cytochrome p450 2d6 to a more potent opioid analgesic, morphine. As we all know morphine provides good pain relief but it is also associated with serious adverse effects such as drowsiness and respiratory depression. Now an individual who is a rapid metaboliser would end up converting codeine to morphine at a very fast rate. This leads to buildup of morphine and a greater risk of adverse effects.
Skip to 4 minutes and 54 secondsIn contrast, individuals whose genetic makeup leads them to be slow metabolisers end up producing morphine at a slower rate and therefore they have poorer pain relief.
Skip to 5 minutes and 20 secondsNow, there's also variation in excretion of the drug. Metformin is a drug that does not undergo liver metabolism but it's actually eliminated in urine through a process known as active tubular secretion. And there are organic cation transporters here which help to clear metformin from the human body. Genetic variation in these transporters means that there are differences amongst individuals in how well they clear metformin from the body through the urinary tract. So what are the clinical implications of variations in pharmacokinetics stemming from these genetic differences?
Skip to 6 minutes and 4 secondsWell, genetic variation can lead to measurable differences in half-life, clearance of the drug, buildup of toxic metabolites, and even non activation of a prodrug, which is an inert precursor that needs conversion to the active molecule in the body. Nevertheless, despite these potential sites of variation, genetic testing for pharmacogenetic adjustments have not been clinically validated. This may be because there are many other factors that affect dosing regimens. Clinicians have many other ways of adjusting individual doses without resorting to looking at genetic information. For instance, a clinician could take a blood sample to measure the actual drug concentration in the patient. There may well be also other markers for drug response that they could use.
Skip to 7 minutes and 16 secondsEqually, the dosing regimen could be adjusted for a patient. For instance - step titration, starting from a low dose and gradually moving upwards until the desired response is obtained, while carefully monitoring for any adverse effects. Now, there are some drugs to have good benefit and little harm across a wide range of doses and in these cases, detailed measurement of pharmacokinetics is not a major issue. These drugs have a good benefit/harm balance and it's not essential to adjust the doses based on genetic variation. And finally, if there are drugs which have difficult pharmacokinetics, clinicians may well prefer alternative treatment options that have far more predictable actions in the human body.
Skip to 8 minutes and 21 secondsSo, in summary, although we have demonstrated that genetic variation can influence pharmacokinetics, particularly in areas such as absorption, metabolism and elimination, and that indeed cytochrome p450 enzyme systems are a major contribution to the genetic diversity and variation in pharmacokinetics, there are actually currently no genetically guided strategies tailored to individual patients that are widely used in clinical practice at the present time.
Genetics and pharmacokinetics
This tutorial by Professor Yoon Loke will explain how genetic variation can affect how the body handles drugs.
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