Our digestive physiology can be quite a handful at times. Especially when it comes to taking medicines to help treat illnesses. We have this awesome organ which you should all have heard of - the liver - and the liver sees fit to clean up the blood, and modify anything coming into the body.
Xenobiotics are chemicals inside us which aren’t naturally meant to be there. These could well be poisons and narcotics. Or they could be helpful medicines. The liver evolved during a time without pharmacies, as did most of our organs… well all of our organs, to be exact. So as a result, the liver sees helpful chemicals (which is all drugs really are) to be just the same as unhelpful ones. The liver has a system in place to deal with foreign chemicals which shouldn’t be there (xenobiotics) and the liver doesn’t really care what they are. The liver produces vast quantities of these enzymes called Cytochrome P450’s. I’ll just refer to them as P450’s. P450’s aren’t very specific and will work on a whole host of foreign chemicals, so they’re prepared for anything. They’re not the be-all-end-all of xenobiotic metabolism, there are also other enzymes such as Alcohol Dehydrogenases which deal with ethanol from your night out. However, there are lots of different types of P450 in you, and they all deal with different types of xenobiotics. Structurally, they’re pretty similar, and they’ve just had slight variations over the course of evolution to adapt them to dealing with a wider, more diverse range of xenobiotics, so you don’t have to get sick over some of the junk you take in with your food.
But as I said, helpful medicines also get metabolised by these enzymes. They get modified, so they’re more soluble in the blood and are urinated out more easily. Most drugs which are taken orally are going to pass through the liver, and are going to have to get past these enzymes. Why? Well, the hepatic portal system of course. All digested material from the small intestine enters the blood flow of the hepatic portal vein, and is thus transported straight to the liver for detoxification and modification. It is only once all this digested material has been processed by the liver, can it enter general circulation and go to where it’s needed. Some substances are absorbed before the small intestine so they may bypass this processing, and that’s something pharmacologists bear in mind when designing drugs. Especially oral drugs - which may be the most economically viable and most convenient, but they do have to go through the proverbial mill in order to carry out their function.
The P450’s will act on the incoming drugs which have just been absorbed in the small intestine and they will metabolise them, and modify them. Sometimes the modifications don’t do much, some drugs will happily continue and do their job. Other drugs will become inactivated by the enzymes, meaning that a very small amount actually enters circulation - meaning you need to take more drug, which could mean an increased risk of possible side effects.
Some drugs are modified and their function changes. This can be bad. In the case of paracetamol, a toxic metabolite is produced. A type of P450 called CYP2E1 deals with paracetamol in this way, and it increases the risk of paracetamol poisoning. Thing is, this CYP2E1 enzyme is only present under certain circumstances. Production of this enzyme is stimulated by alcohol. As a result, alcoholics should avoid using paracetamol as they’re at greater risk of being poisoned by it, rather than helped by it. P450’s vary between people. Some are induced by environmental factors (like the alcohol), others are hereditary. There are whole races who respond differently to drugs in comparison to other races, simply because their gene pools don’t include the expression of certain P450’s. Which means you can inherit susceptibility to drugs from your parents (though this isn’t the case with all drugs).
So pharmacologists and other scientists need to bear these curious enzymes in mind when designing drugs - and doctors need to bear in mind that a patient may have the wrong genetics to deal with a drug. Of course, pharmacists have many methods to get round this, some more effective than others. For example; morphine. Morphine can be taken as Diamorphine (a.k.a heroin). Diamorphine is metabolised to form morphine which is the painkilling drug we want to work in our bodies. Drugs which are given in a less active form, and are metabolised in the body to form the active drug are known as pro-drugs.
This is where pharmacology and genetics really meet. And from the genetics end of things, scientists are working on developing the technology for the $1000 genome. The $1000 genome is the technology to be able to sequence your entire DNA, or my entire DNA for $1000 or under (or £643 at the current exchange rate). This technology may well cause a revolution in medicine, spawning the discipline of Personalised Medicine. With this, a doctor or geneticist can look at your DNA sequence and tailor a medical treatment specifically for you. They can look at which P450’s you’re expressing and give you the drugs which can work best with your physiology, or diagnose potential future neurodegenerative diseases by looking for predispositions for disease in your DNA.
I must say, biochemistry does rock.