Human Drug Metabolism (III)

This is my third post about this book. You can read my previous posts here and here. In this post I have covered material from chapter 7, dealing with ‘factors affecting drug metabolism’.

“Data from animal studies in one country are usually comparable with that of another, provided the animal species and strain are the same. This provides a consistent picture of the basic pharmacological and toxicological actions of a candidate drug in a living organism […] it has been obvious since animal testing began that there would be large differences in the way a drug might perform in man compared with animal species […]. Unfortunately, there is no experimental model yet designed that can not only consider human biochemistry and physiology, but also the effects of age, smoking, legal and illegal drug usage, gender, diet, environment, disease and finally genetic variation. Indeed, many clinical studies have revealed enormous differences in drug clearance and pharmacological effect even in age, sex and ethnically matched individuals. In effect, this means that the first year or so of a drug’s clinical life is a vast, but monitored experiment, involving hundreds of thousands of patients and there is no guarantee of success.”

“Most biotransformational polymorphisms that might potentially cause a problem clinically are due to an inability of those with defective enzymes to remove the drug from the system. Drug failure can occur if the agent is administered as a pro-drug and requires some metabolic conversion to an active metabolite. Drug accumulation can lead to unpleasant side effects and loss of patient tolerance for the agent. […] Overall, there are a large number of factors that can influence drug metabolism, either by increasing clearance to cause drug failure, or by preventing clearance to lead to toxicity. In the real world, it is often impossible to delineate the different conflicting factors which result in net changes in drug clearance which cause a drug to fall out of, or climb above, the therapeutic window. It may only be possible clinically in many cases to try to change what appears to be the major cause to bring about a resolution of the situation to restore curative and non-toxic drug levels.”

“Most population studies of human polymorphisms list the allelic frequency, that is, how many of an ethnic group contain the alleles in question. […] The actual haplotypes in the population, that is, which individuals express which combinations of alleles, are not the same as the population allelic frequency. […] If an SNP or a combination of SNPs is a fairly mild defect in the enzyme when it is homozygously expressed, then the heterozygotes will show little impairment and the polymorphism may be clinically irrelevant. With other SNPs, the enzyme produced may be completely non-functional.  Homozygotes will be virtually unable to clear the drug and heterozygotes will show impairment also. There are also smaller populations of UMs, or ultra rapid metabolizers which may have a feature of their enzyme which either makes it super efficient or expressed in abnormally high amounts. […] Phenotyping will group patients in very broad EMs [extensive metabolizers], IMs [intermediate metabolizers] or PM [poor metabolizers] categories, but will be unable to distinguish between heterozygous and homozygous EMs. Although genotyping may be very helpful in dosage estimation in the initiation of therapy, there is no substitute for the normal process of therapeutic monitoring, which is effectively phenotyping the individual in the real world in terms of maximizing response and minimizing toxicity.”

“it is clear that there is a vast amount of genetic variation across humanity in terms of biotransformational capability and so the idea that in therapeutics, ‘one size fits all’ is not only outdated, but fabulously naïve. […] Unfortunately, detecting and responding successfully to human biotransformational polymorphisms has proved to be extremely problematic. In terms of polymorphism detection, this area is a classic illustration of how the exploration of the human genome with powerful molecular biological tools may unearth many apparently marked polymorphic defects that may not necessarily translate into a measurable clinical impact in terms of efficacy and toxicity. In reality, many more scientists have the opportunity to discover and publish such polymorphisms in vitro, than there are clinical scientists, resources and indeed cooperative volunteers or patients in sufficient quantity to determine practical clinical relevance.”

the CYP3A group (chromosome 7) metabolize around half of all drugs […] variation in the metabolism of CYP3A substrates […] can be up to ten-fold in terms of drug clearances and up to 90-fold in liver protein expression. […] It is likely that the full extent of the variation in CYP3A4 is still to be discovered […] While it is thought that CYP3A4 is not subject to an obvious major polymorphism, CYP3A5 definitely is. […] *3/*3 individuals form no serviceable CYP3A5. Functional CYP3A5 is found in around 20 per cent of Caucasians, half of Chinese/Japanese, 70 per cent of Hispanics and more than 80 per cent of African Americans.”

“A particularly dangerous polymorphism clinically was identified in the 1980s for one of the methyltransferases. The endogenous role of S-methylating thiopurine S-methyltransferase (TPMT) is not that clear, but […] [t]hese drugs are […] effective in some childhood leukaemias […] TPMT highlights the genotyping/phenotyping issue mentioned earlier in the management of patients with polymorphisms. Genotyping will reveal the level of TPMT expression that should be expected in the otherwise healthy patient. However, there are many factors which impact day-to-day TPMT expression during thiopurine therapy. […] Hence, what might be predicted from a genotype test may bear little resemblance to how the enzyme is performing on a particular day in a treatment cycle. So clinically, it is preferred to test actual TPMT activity.”

“Understanding of sulphonation and its roles in endogenous as well as xenobiotic metabolism is not as advanced compared with that of CYPs; however, the role of SULTs in the activation of carcinogens is becoming more apparent. One of the major influences on SULT activity is their polymorphic nature; in the case of one of the most important toxicologically relevant SULTs, SULT1A1, this isoform exists as three variants, SULT1A1*1 (wild-type), SULT1A1*2 and SULT1A1*3. The *1 variant allele is found in the majority of Caucasians (around 65 per cent), whilst the *2 variant differs only in the exchange of one amino acid for another. This single amino acid change has profound effects on the stability and catalytic activity of the isoform. The *2 variant is found in approximately 32 per cent of Caucasians and catalytically faulty […] About 9 in 10 Chinese people have the *1 allele and about 8 per cent have allele *2. About half of African-Americans have *1 and a third have *2. Interestingly, there is a *3 which is rare in most races but accounts for more than 22 per cent of African Americans. There is also considerable variation in SULT2A1 and SULT2B1, which are the major hydroxysteroid sulphators in the body, which may have implications for sex steroid and cholesterol handling. […] from the cancer-risk viewpoint, a highly active SULT1A1 *1 is usually an advantage in that it usually removes reactive species rapidly as stable sulphates. With some agents it is problematic as certain carcinogens such as acetylfluorene are indirectly activated to reactive species by SULTs. In addition, protective dietary flavonoids […] are also rapidly cleared by SULT1A1 *1, so there is a combination of production of toxins and loss of protective dietary agents. In terms of carcinogenesis risk, SULT1A1*2 could be a liability as potentially damaging substrates such as electrophilic toxins cannot be cleared rapidly. However, in some circumstances the *2 allele can be rather protective as […] it also allows protective agents [to] remain in tissues for longer periods. The combinations are endless and so it is often extremely difficult to predict risks of carcinogenicity for individuals and toxin exposures.”

GSTs are polymorphic and much research has been directed at linking increased predisposition to cytotoxicity and carcinogenicity with defective GST phenotypes. Active wild-type GSTMu-1 is found in around 60 per cent of Caucasians, but a non-functional version of the isoform is found in the remainder. […] GST-M1 null (non-functional alleles) can predispose to risks of prostate abnormalities and GST Pi is subject to several SNPs and many attempts have been made to link these SNPs with the consequences of failure to detoxify reactive species, such as the risk of lung cancer. […] Carcinogenesis may be due to a complex mix of factors, where different enzyme expression and activities may combine with particular reactive species from specific parent xenobiotics that lead to DNA damage only in certain individuals. Resolving specific risk factors may be extremely difficult in such circumstances. […] in cancer chemotherapy, there is evidence that the presence of GST-M1 and GST-T1 null (non-functional) alleles predisposes children to a six-fold higher level of adverse events usually seen with antineoplastic drugs, such as bone marrow damage, nephrotoxicity and neurotoxicity.”

“The effects of age on drug clearance and metabolism have been known since the 1950s, but they have been extensively investigated in the last 20 or so years. It is now generally accepted that at the extremes of life, neonatal and geriatric, drug clearance can be significantly different from the rest of humanity. In general, neonates, i.e. those less than four weeks old, cannot clear certain agents due to immaturity of drug metabolizing systems. Those over retirement age cannot clear the drugs due to loss of efficiency in their metabolizing systems. Either way, the net result can be toxicity due to drug accumulation. […] It seems that the inability of older people to clear drugs is not necessarily related to the efficacy of their CYP-mediated oxidations, which are often not much different from that of younger individuals. Studies with the major CYPs in vitro have revealed that CYP2D6 is unaffected by age, as are most other CYPs, with the exception of CYP1A2, which does decline in activity in the elderly. […] In general, there is little significant change in the inducibility in most CYPs, or in the capability of conjugation systems in vitro. […] there are significant changes in the liver itself, as it decreases in mass and its blood flow is reduced as we age. This occurs at the rate of around 0.5–1.5 per cent per year, so by the time we hit 60–70, we may have up to a 40 per cent decline in liver blood flow compared with a 30-year-old. Other factors include gradual decline in renal function, increased fat deposits and reduction in gut blood flow, which affects absorption. […] The problem arises that the drug’s bioavailability increases due to lack of first-pass clearance; this means that from a standard dose, blood levels can be considerably higher than would be expected in a 40-year-old. This can be a serious problem in drugs with a narrow TI, such as antiarrhythmics. In addition, average doses of warfarin required to provide therapeutic anticoagulation in the elderly are less than half those required for younger people. The person’s lifelong smoking and drinking habits, as well as older individuals ’ sometimes erratic diet also complicate this situation. Among the drugs cleared more slowly in older people are antipsychotics, paracetamol, antidepressants, benzodiazepines, warfarin, beta-blockers and indomethicin.”

“Thousands of polyphenols are found in plants, vegetables, fruit, as well as tea, coffee, wine and fruit juices. […] Flavonoids such as quercetin and fisetin are excellent substrates for COMT, so competitively inhibiting the metabolism of endogenous catecholamine and catechol oestrogens. Quercetin and other polyphenols are found in various foods such as soy (genestein) and they are potent inhibitors of SULT1A1 which sulphate endogenous oestrogens, so potentiating the effects of oestrogens in the body. Many of these flavonoids and isoflavonoids are manufactured and sold as cancer preventative agents; however, it is more likely that their elevation of oestrogen levels may have the opposite effect in the long term. It is also likely that various polyphenols influence other endogenous substrates of sulphotransferases, such as thyroid hormones and various catecholamines. It is gradually becoming apparent that polyphenols can induce UGTs, indeed; it would be surprising if they did not. […] Overall, it is likely that there are a large number of polyphenols that are potent modulators of CYPs and conjugative enzymes. […] It is clear that diet can substantially modulate biotransformation […] As to the effects on prescription drugs, […] abrupt changes in a person’s diet may significantly alter the clearance of drugs and lead to loss of efficacy or toxicity.”

In general, experimental or ‘probe’ drugs […] which are used to study the activities of a number of CYPs, are metabolized more quickly by women than men. This is allowing for differences in weight, fat distribution (body mass index) and volume of distribution […] It appears that CYP expression is linked to growth hormone (GH) and about the same amount is secreted over 24 hours in both sexes. In animals the pattern of release of the hormone is crucial to the effects on the CYPs; in females, GH is secreted in small but more or less continuous pulses, while males secrete large pulses, then periods of no secretion. The system is thought to be similar in humans. […] Little is known of the effects of the menopause and hormone replacement, where steroid metabolism changes dramatically. It is highly likely that these events could have profound effects on female drug clearance. […] females in general are more susceptible to drug adverse reactions than males, especially hepatotoxic effects.”

“For those chronically dependent on ethanol their CYP2E1 levels can be ten-fold higher than non-drinkers and they would clear CYP2E1 substrates extremely quickly if they chose to be sober for a period of time. This may lead to the accumulation of metabolites of the substrates. It is apparent that alcoholics who are sober can suffer paracetamol (acetaminophen)-induced liver toxicity at overdoses of around half that of non-drinkers, which is due to CYP2E1 induction. […]  the vast variation in ADH [alcohol dehydrogenase] catalytic activity across the human race is mainly due to just a few SNPs that profoundly change the efficiency of the isoforms. ADH1B/*1 is the most effective variant and is the ADH wild-type […] Part of a ‘successful’ career as an alcoholic depends possessing the ADH1B/*1 isoform. The other defective isoforms are found in low frequencies in alcoholics and cirrhotics. […] in the vast majority of individuals, whatever their variant of ADH, they are able to process acetaldehyde to acetate and water, as the consequences of failing to do this are severe. With ALDH, the wild-type and gold standard is ALDH2*1/*1, which has the highest activity of all these isoforms and is the second essential component for an alcoholic career. […] the variant ALDH2*1/*2 has less than a quarter of the wild-type’s capacity and is found predominantly in Eastern races. The variant ALDH2*2/*2 is completely useless and renders the individuals very sensitive to acetaldehyde poisoning, although the toxin is removed eventually by ALDH1A1 which does not seem to be affected by polymorphisms. In a survey of 1300 Japanese alcoholics, there was nobody at all with the ALDH2*2/*2 variant. […] Women are much more vulnerable to ethanol damage and on average die in half the time it generally takes for a male alcoholic to drink himself to death. Women drink much less than men also – one study indicated that a group of women consumed about 14,000 drinks to induce cirrhosis, whilst men required more than 44,000 to achieve the same effect. Ethanol distributes in total body water only, so in women their greater fat content means that blood ethanol levels are higher than men of similar weight and age.

September 15, 2016 - Posted by | books, genetics, medicine, Pharmacology

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