Slow metabolisers

Omeprazole 20 mg daily for 8 days had no effect on the pharmacokinetics of phenacetin, or paracetamol derived from phenacetin, in 10 healthy subjects, except that the peak plasma level of phenacetin was higher. There was no change in the metabolism (oxidative and conjugative) of phenacetin or derived paracetamol. In another study, omeprazole 40 mg daily for 7 days had no effect on the formation of thioether metabolites of paracetamol in 5 rapid and 5 slow metabolisers of 5-mephenytoin [a probe drug for CYP2C19 activity, see Genetic factors in drug metabolism , (p.4)].3... 

The documentation is limited, but a clinieally important and potentially serious interaction is established between isoniazid and carbamazepine. Toxicity can develop quickly (within 1 to 5 days) and also seems to disappear quickly if the isoniazid is withdrawn. Concurrent use should not be undertaken unless the effects can be closely monitored and suitable downward dosage adjustments made (a reduction to between one-half or one-third was effective in 3 patients ). It seems probable that those who are slow metabolisers of isoniazid may show this interaction more quickly and to a greater extent than fast metabolisers. ... 

Serum phenytoin levels are markedly reduced by rifampicin, but can be raised by isoniazid. Those who are slow acetylators (slow metabolisers) of isoniazid may develop phenytoin toxicity if the dosage of phenytoin is not reduced appropriately. If rifampicin and isoniazid are given together, serum phenytoin levels may fall in patients who are fast acetylators of isoniazid, but may occasionally rise in those who are slow acetylators. Clofazimine may reduce serum phenytoin levels. 

Rifampicin (a known potent liver enzyme inducer) increases the metabolism and clearance of the phenytoin from the body so that a larger dose is needed to maintain adequate serum levels. Isoniazid inhibits the liver microsomal enzymes that metabolise phenytoin, and as a result the phenytoin accumulates and its serum levels rise. Only those who are slow acetylators (slow metabolisers) of isoniazid normally attain blood levels of isoniazid that are sufficiently high to cause extensive inhibition of the phenytoin metabolism. Fast acetylators (fast metabolisers) remove the isoniazid too quickly for this to occur. Acetylator status is genetically determined. Thus some individuals will show a rapid rise in phenytoin levels, which eventually reaches toxic concentrations, whereas others will show only a relatively slow and unimportant rise to a plateau within, or only slightly above the therapeutic range. 

The interaction with phenytoin and isoniazid alone is well documented, well established, clinically important and potentially serious. About 50% of the population are slow or relatively slow metabolisers of isoniazid, but not all of them develop serum phenytoin levels in the toxic range. The reports indicate that somewhere between 10 and 33% of patients are at risk. This adverse interaction may take only a few days to develop fully in some patients, but several weeks in others. Therefore concurrent use should be very closely monitored, making suitable dosage reductions as... 

The toxicity of an insecticide not only depends upon its molecular structure but also the way it is metabolised. A good example of this is Malathion (77), which is metabolised very differently by insects and humans and is therefore only toxic to insects. The mildly active Malathion (77) is rapidly oxidised in insects converting it into the strongly active oxidation product 79 (Equation 84), and this is only broken down very slowly by hydrolysis to give the weakly active 81. In contrast, oxidation of Malathion in mammals is slow, but hydrolysis of the ester group occurs very rapidly to give the inactive non-toxic compound 80 (Equation 84).1,169... 

Readily absorbed from the GI tract. Food slows the rate of absorption but not the total bioavailability. Extensively bound to plasma proteins and substantial concentrations are found in synovial fluid. Metabolised mainly by conjugation with glucuronic acid and excreted mainly in the urine. 

It is a slow acting alkylating agent. After oral administration, it shows adequate and reliable absorption and almost completely metabolised. 

Disposition in the Body. Rapidly absorbed after oral administration. It penetrates into the cerebrospinal fluid to produce concentrations about one-half of those in blood. Metabolised by TV -acetylation, the extent of which is genetically determined in slow acetylators about 15% of the sulfamerazine in the blood is in the form of the acetyl derivative compared with 35% in rapid acetylators. About 60% of a dose is excreted in the urine in 48 hours approximately half of the excreted material is in the form of the acetyl derivative. 

Pharmacokinetics. Benzodiazepines are effective after administration by mouth but enter the circulation at very different rates that are reflected in the speed of onset of action, e.g. alprazolam is rapid, oxazepam is slow (Table 19.8). The liver metabolises them, usually to inactive metabolites but some compoimds produce active metabolites, some with long t) which greatly extends drug action, e.g. chlordiazepoxide, clorazepate and diazepam all form desmethyldiazepam (t/ 80 h). 

Pharmacokinetics. Amiodarone is effective given orally its enormous apparent distribution volume (701/kg) indicates that little remains in the blood. It is stored in fat and many other tissues and the t) of 54 days after multiple dosing signifies slow release from these sites (and slow accumulation to steady state means that a loading dose is necessary, see Table 24.1). The drug is metabolised in the liver and eliminated through the biliary and intestinal tracts. 

Cycloate is rapidly metabolised in the roots and leaves of sugar beet—3 days after treatment no unchanged compound can be detected. Metabolic degradation results in amines, COj, amino acids, sugars and other naturally occurring plant constituents. In sensitive plants this metabolism is slow, presumably it is the main reason for selectivity. Cycloate is rapidly degraded in the soil by the microbial pathway. At normal rates of application it is degraded in 3-6 weeks. 

Not fully understood. The suggestion is that methylphenidate acts as an enzyme inhibitor, slowing the metabolism of the phenytoin by the liver and leading to its aeeumulation in those individuals whose drug metabolising system is virtually saturated by phenytoin. 

The small intestine is the major site of absorption for levodopa, and delayed gastric emptying appears to result in low plasma levodopa levels, probably because levodopa can be metabolised in the stomach. In theory, antacids may reduce gastric emptying time, and increase levodopa absorption. It is not known why antacids reduced absorption from the slow-re-lease preparation. ... 

Coumarin anticoagulants are widely used in therapy. They are absorbed relatively quickly, but their effect is slow. They are bound to plasma proteins and released in free form into the liver where they are metabolised. Therefore, in elucidating the therapeutic usefulness of these drugs, the bioavailability, rates of absorption and metabolism must both be considered. From this point of view, the relationship between structure and dose response is tabulated (Table 3.10). 

The relationship between the chemical structure and toxicity of various coumarin insecticides and anthelmintics are compiled (Table 3.13), and for comparison, some other related compounds are also tabulated. The mammalian toxicity of these compounds is moderate, and their selective action on insects is coimected with differences in metabolism. In mammals these chemicals are probably rapidly metabolised by hydrolysis between the aromatic and phosphate groups, whereas in insects by slow oxidation of the phosphorothionate to phos-... 

Elsharkawy AM, SchwabU, McCarron B, BurtAD, Daly AK, Hudson M, Masson S (2013) Efevirenz induced acute liver failure requiring liver transplantation in a slow drug metaboliser. J Clin Vrol 58 331-333... 

After PFOS enters the human body orally, it is relatively easily absorbed and distributed mainly to the liver and blood serum, but is not metabolised. It is excreted in the urine and faeces, but its excretion is very slow. It is estimated that half of the received dose may be removed from the human body in approximately 9 years. PFOA can enter the human body not only orally, but also (to a lesser extent) by inhalation and dermal absorption. It is not accumulated in the adipose tissue, but is covalently bound to macromolecules, especially proteins in the liver, plasma and testes of males. It is not metabolised and is excreted from the body in urine and faeces. It is estimated that half of the ingested amount can be removed from the human body in 1-3 years. 

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