Human Drug Metabolism (II)

My first post covering Coleman’s excellent book can be found here, and here you can read my goodreads review of the book; I think it makes sense to read those things before reading this post, if you have not already done that. As I believe I’ve previously mentioned (?) most non-fiction books I read, including those I do not blog, usually get a goodreads review, and actually I’m much more active on goodreads these days than I am on this blog. I have considered cross-posting goodreads reviews here on the blog, but I decided it might be best to just keep these things separate for the time being. I might change my mind about this, though; I don’t like how inactive the blog has become during the last few months, and goodreads reviews I’ve already written take almost no work to cross-post, so this would be an easy way to at least get some ‘activity’ here.

The book includes a lot of information that really pretty much everybody would be likely to benefit from knowing (how many people for example live their entire lives without consuming any alcohol, tobacco, or medical drugs? If you’ve ever consumed any of these things, the book has material of relevance included in the coverage…). I repeat myself here, but  some of the general observations included in the following seem to me to be important takeaways from the book: Drugs work (sometimes very) differently in different people, they interact with different things, including innocuous things like what you eat and drink and whether you exercise or not; drugs may interact with each other, in a very confusing variety of ways; some drugs are metabolized differently in people who have taken the drug for a while (‘induction’), compared to how the drug might be metabolized in someone who’s not taken the drug before (drug-naïve), and sometimes the ability to metabolize the drug faster/more efficiently may be lost (inhibition) because of a third factor, such as e.g. another drug or a dietary factor, which can be very dangerous (an improved ability to metabolize the drug because of habituation may also be lost due to non-consumption of the drug for some time, leading to a ‘reset’ of the metabolic pathway of relevance, an important factor in an abuse context where this can lead to overdose); there are huge racial and genetic differences in terms of how specific drugs are metabolized; the consequences of getting too much of a specific drug (toxicity) tend to be foreseeably different from the consequences of getting not enough of a drug (drug failure); efficient metabolism of a drug may depend upon the body’s ability not just to transform the xenobiotic compound into something useful, but also the ability to get rid of sometimes really quite toxic metabolites which might be created along the way as the body tries to get rid of that thing you just injected/ingested/etc. Many people don’t consider herbal remedies to be ‘real drugs’ and so neglect to tell their medical practitioner that they’re taking them/have recently stopped taking them, despite some of these having the potential to cause quite serious drug interactions (even if nothing is taken but herbal remedies; St. John’s Wort + kava kava = acute hepatitis? As noted in the book, “One point important to emphasize, is that assuming various herbal remedies do contain active and potent substituents, there is virtually nothing known clinically about what effects mixing herbal remedies might have, in terms of pharmacology and toxicity. This area is unfortunately left for patients to discover for themselves”).

This book is not ‘the whole story’ about drug metabolism and related stuff, it just scratches the surface, but the coverage serves to make it clear to you just how much stuff is to be found ‘below the surface’, and this is something I really like about the book. It makes you appreciate how little you know and how complex this stuff is. People write 500+ page textbooks like this one simply about CYP subtypes (I came across a different 1000+ page textbook also about a CYP subtype while reading the book so I know this one is hardly unique, but unfortunately I did not bookmark the book and I didn’t find the book after a brief search for it – but take my word for it, those books are out there…) and alcohol metabolism, they write 700 page textbooks about the side effects of psychiatric drugs (not the intended effects, that is – the side effects!) they write 800 page textbooks about aspirin and related drugs and about how drugs affect the liver… I know that in some circles it’s somewhat common for people to ‘experiment’ with various drugs and substances, illicit or otherwise; I also assume that most people who do this sort of thing have little idea what they’re actually doing and are likely taking a lot of risks the very existence of which they’re likely not aware of. Simply because there’s just so much stuff you need to know to even have a proper concept of what you’re doing when you’re dealing with how the human body works and how it responds to foreign substances we might choose to introduce into it. It might be that they wouldn’t care even if they knew because you’re probably rather low in risk aversion if you engage in that sort of experimentation in the first place (I incidentally am highly risk averse), but I do find it curious.

I have added some observations from the middle of the book below.

“Although there is growing awareness of the clinical problems posed by P-gp [P-glycoprotein] inhibition on drug bioavailability and toxicity, until recently it was very difficult to generalize and predict which classes of drug might be inhibitors of P-gp. […] There are dozens of drugs which are known inhibitors of P-gp […] it is often difficult to establish what contribution cellular transport systems make to bioavailability. Indeed, it is emerging that one of the reasons for the very wide variety of drug bioavailability in modern medicine could be the sheer number of possible inhibitors and substrates that exist for P-gp in the diet, such as a number of natural products like the flavonols, which can be as potent as cyclosporine or verapamil as P-gp inhibitors. Natural dietary inhibitors have advantages in their general lack of toxicity, but the basic problem of a lack of predictability in their effects on P-gp substrates remains. Since no two people’s diets are identical, the impact of P-gp modulation on drug absorption could be simply too complex to unravel.”

“the objectives of metabolizing systems could be summed up thus:
• To terminate the pharmacological effect of the molecule.
• Make the molecule so water-soluble that it cannot escape clearance, preferably by more than one route to absolutely guarantee its removal.
These objectives could be accomplished by:
• Changing the molecular shape so it no longer binds to its receptors.
• Changing the molecular lipophilicity to hydrophilicity to ensure high water solubility.
• Making the molecule larger and heavier, so it can be eliminated in bile as well as urine.
• Efflux pump systems, which ensure that a highly water-soluble metabolite actually leaves the cell to enter the bloodstream, before it is excreted in bile and urine. […]
CYP-mediated metabolism can increase hydrophilicity, but it does not always increase it enough and it certainly does not make the molecule any bigger and heavier, indeed, sometimes the molecule becomes lighter […] CYP-mediated metabolism does not always alter the pharmacological effects of the drug either […] However, CYPs do perform two essential tasks: the initial destabilization of the molecule, creating a ‘handle’ on it. […] CYPs also ‘unmask’ groups that could be more reactive for further metabolism. […] CYP-mediated preparation can make the molecule vulnerable to the attachment of a very water-soluble and plentiful agent to the drug or steroid, which accomplishes the objectives of metabolism. This is achieved through the attachment of a modified glucose molecule (glucuronidation), or a soluble salt such as a sulphate (sulphation) [see also this] to the prepared site. Both adducts usually make the drug into a stable, heavier and water-soluble ex-drug. […] with many drugs, their stability and lipophilicity mean that their clearance must take more than one metabolic operation to make them water-soluble.”

PXR [Pregnane X receptor], CAR [constitutive androstane receptor] and FXR [Farnesoid X receptor] are […] part of the process whereby the liver can sense whether its own metabolic capacity and physical size is sufficient to respond to homeostatic demands. Hence, alongside various growth factors, the NRs [nuclear receptors] facilitate the amazing process whereby the liver regenerates itself after areas of the organ are removed or damaged. […] As CYPs, UGTs [Glucuronosyltransferases], other biotransforming systems and efflux transporters are meeting the same xenobiotic or endobiotic stimuli in different tissues and degrees of exposure, it is logical that the […] receptor systems integrate and coordinate their responses. […] These multi-receptor mechanisms enable levels of induction to be customized for individual tissues to deal with different chemical threats. Essentially, according to diet, chemical and drug exposure, each individual will possess a unique expression array of UGTs and CYPs which will be constantly fine-tuned throughout life.”

“Sulphonation is accomplished by a set of enzyme systems known as sulphotransferases (SULTs) and they are found in most tissues to varying degrees of activity. […] The general aim of sulphonation is to make the substrate more water-soluble and usually less active pharmacologically. Sulphonated molecules are more readily eliminated in bile and urine. […] All SULTs are subject to genetic polymorphisms, with a high degree of individual variation in their expression and catalytic activities […] Regarding classification of the superfamily of SULTs, it is assumed that 47 per cent amino acid sequence homology is indicative of same family members and 60 per cent homology for subfamily members. To date, there are 47 mammalian SULT isoforms so far discovered, which are derived from ten human sulphotransferase gene families […] knowledge of the role of NRs and AhR [Aryl hydrocarbon receptor] in human SULT expression has progressed in animals but not really in humans. This is partly due to the fact that rodent SULT profiles are quite different to ours […] Many studies have been carried out in rodents, which have produced rather contradictory results […] It seems that whilst SULTs in general are not as responsive to inducers as CYPs and UGTs, their basal expression is much higher, although interindividual expression does vary considerably and this may have severe toxicological consequences, in terms of xenobiotic toxicity and carcinogenicity. There is also some evidence that diet is a strong influence on individual SULT profiles.”

“One of the main problems with the oxidation of various molecules by CYP enzymes is that they are often destabilized and sometimes form highly reactive products. […] CYPs occasionally form metabolites so reactive that they immediately destroy the enzyme by reacting with it, changing its structure and, therefore, its function. […] The most dangerous forms of reactive species are those that evade UGTs and SULT enzymes, or are inadvertently created by conjugation processes. These species escape into the cytosol and even into the nucleus, where potentially carcinogenic events may result. […] CYPs are not the only source of reactive species generated within cells. Around 75 per cent of our food intake is directed at maintaining our body temperature and a great deal of energy must be liberated from the food to accomplish this. Cells derive the vast majority of their energy through oxidative phosphorylation and this takes place in […] the mitochondria. […] In cells almost all the oxygen we breathe is consumed in oxidative phosphorylation, forming ATP, heat and reactive oxidant species in the mitochondria that could cause severe damage to the structure and function of the cell if they were allowed to escape. So all cells, particularly hepatocytes, have evolved a separate system to accommodate such reactive toxic products and this is based on a three amino acid (cysteine, glycine and glutamate) thiol known as glutathione, or GSH. Thiols in general are extremely effective at reducing and thus ‘quenching’ highly reactive, electrophilic species. […] if cells are depleted of GSH by blocking its synthesis (by using buthionine sulphoxime), cell death follows and the organism itself will die in a few days, due to uncontrolled activity of endogenous radicals. […] If GSH levels are not maintained in the cell over a long period of time, the cell wears out more quickly; for example, diabetic complications and HIV infection are linked with poor GSH maintenance.” [I did not know this…]

“There are several enzymes that promote and catalyze the reaction of GSH with potential toxins to ensure that reactive species are actively dealt with, rather than just passive GSH-mediated reduction. Probably the most important from the standpoint of drug metabolism are the GSH-S-transferases [‘GSTs’, which] are the key cellular defence against electrophilic agents formed from endogenous or xenobiotic oxidative metabolism. […] The GSTs are found in humans in several major classes. […] The classes contain several subfamilies […] These enzymes are polymorphic […] and their individual expression ranges from complete absence in some isoforms to overabundance as a response to anticancer therapy. […] The upregulation of GST is a serious problem within cancer therapeutics and resistance to a range of drugs including melphalan and doxorubicin is linked with GST detoxification. Much research has been directed at inhibitors of GST isoforms to reverse or even prevent the development of resistance to anti-neoplastic agents. Unfortunately this strategy has not been successful”

“once xenobiotics have been converted into low-toxicity, higher-molecular-weight and high-water-solubility metabolites by the combination of CYPs, UGTs, SULTs and GSTs, this appears at first sight to be ‘mission accomplished’. However, these conjugates must be transported against a concentration gradient out of the cell into the interstitial space between cells. Then they will enter the capillary system and thence to the main bloodstream and filtration by the kidneys. The biggest hurdle is the transport out of the cell, which is a tall order, as once a highly water-soluble entity has been created, it will effectively be ‘ion-trapped’ in the cell, as the cell membrane is highly lipophilic and is an effective barrier to the exit as well as entry of most hydrophilic molecules. […] failure to remove the hydrophilic products of conjugation reactions [from the cells] can lead to:
• toxicity of conjugates to various cell components;
• hydrolysis of conjugates back to the original reactive species;
• inhibition of conjugating enzymes.
If the cell can manage to transport them out, then they should be excreted in urine or bile and detoxification can proceed at a maximal rate. […] Consequently, an impressive array of multi-purpose membrane bound transport carrier systems has evolved which can actively remove hydrophilic metabolites and many other low molecular weight drugs and toxins from cells. The relatively recent […] term of Phase III metabolism has been applied to the study of this essential arm of the detoxification process. […] The main thrust of research into efflux transporters has been directed at the ABC-type transporters [this link actually has quite a bit of content, unlike some of the other wiki articles on these topics], of which there are 48 genes that code of a variety of ATP-powered pumps.”

“it is clear that the whole process of detection, metabolism and elimination of endobiotic and xenobiotic agents is minutely coordinated and is responsive to changes in load in individual tissues. The CYPs, UGTs, MRPs [Multidrug Resistance Proteins] and P-gp are all tightly regulated through the NR system of PXR, CAR, FXE, PPAR α, LXR etc, as well as the AhR receptor system [does it even make sense to keep adding links here? I’m not sure it does…]. Some enzyme/pump processes are closely linked, such as CYP3A4 and P-gp, as inducers powerfully increase both systems capacity. The reactive species protection ‘arm’ of biotransformation is also controlled through a separate but almost certainly ‘cross-talking’ Nrf2/Keap1 system which coordinates not only the interception of reactive species by GSTs, but also the supply of their GSH substrate, UGTs and the MRPs. This latter coordination is particularly relevant in resistance to cancer chemotherapy and happens because overexpression of any one entity alone cannot rid the cell of the toxin. […] The MRPs, GSH production and GST/UGT activity must be induced in concert. […] much of the integration and coordination of detoxification processes remains to be uncovered”.

Chapter 7, about ‘factors affecting drug metabolism’, has some very interesting stuff, but I think this post is quite long enough as it is. I might talk about that stuff in detail later on, but I make no promises.

August 9, 2016 - Posted by | books, medicine, Pharmacology

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