Metabolism, slow metabolizers

Depending on the exact nature of the mutation present, the different CYP2D6 isozymes exhibit varying degrees of efficiency in the metabolism of substrate the range includes poor metabolism, slow metabolism, extensive metabolism, and su-perextensive metabolism (Smith and Mendoza 1996). 

Template recognition is the process of finding the most similar sequence. The researcher must choose how to compute similarity. It is possible to run a fast, approximate search of many sequences or a slow, accurate search of a few sequences. Sequences that should be analyzed more carefully are the same protein from a different species, proteins with a similar function or from the same metabolic pathway, or a library of commonly observed substructures if available. 

Although thiosulfate is one of the few reducing titrants not readily oxidized by contact with air, it is subject to a slow decomposition to bisulfite and elemental sulfur. When used over a period of several weeks, a solution of thiosulfate should be restandardized periodically. Several forms of bacteria are able to metabolize thiosulfate, which also can lead to a change in its concentration. This problem can be minimized by adding a preservative such as Hgl2 to the solution. 

Phenytoin s absorption is slow and variable yet almost complete absorption eventually occurs after po dosing. More than 90% of the dmg is bound to plasma protein. Peak plasma concentrations are achieved in 1.5—3 h. Therapeutic plasma concentrations are 10—20 lg/mL but using fixed po doses, steady-state levels are achieved in 7—10 days. Phenytoin is metabolized in the fiver to inactive metabolites. The plasma half-life is approximately 22 h. Phenytoin is excreted primarily in the urine as inactive metabolites and <5% as unchanged dmg. It is also eliminated in the feces and in breast milk (1,2). Prolonged po use of phenytoin may result in hirsutism, gingival hyperplasia, and hypersensitivity reactions evidenced by skin rashes, blood dyscrasias, etc... 

Encainide is almost completely absorbed from the GI tract. Eood may delay absorption without altering its bioavailabiUty. The dmg is rapidly metabolized in 90% of the patients to two principal metaboUtes, 0-demethylencainide (ODE) and 3-methoxy-O-demethylencainide (MODE), while the other 10% metabolize encainide slowly with Htde or no ODE or MODE formed. Encainide, ODE, and MODE are extensively protein bound 75—80% for encainide and ODE and 92% for MODE. Peak plasma concentrations are achieved in 30—90 min. Therapeutic plasma concentrations are very low the concentrations of ODE and MODE are approximately five times those of encainide. The findings with the metaboUtes are significant because ODE is 2—10 times and MODE, 1—4 times more effective than encainide as antiarrhythmics. The half-Hves for encainide in fast and slow metabolizers is 1—2 h and 6—12 h, respectively. The elimination half-life for ODE is 3—4 h and for MODE 6—12 h in fast metabolizers. Excretion occurs through the Hver and kidneys (1,2). 

Adenosine is not active orally, but adrninistered as an iv bolus dmg adenosine rapidly eliminates supraventricular tachycardias within 1—2 min after dosing. The dmg slows conduction through the AV node. Adenosine is rapidly removed from the circulation by uptake into red blood ceUs and vascular endothehal ceUs. Thus the plasma half-life is less than 10 s. Adenosine is rapidly metabolized to inosine or adenosine monophosphate and becomes part of the body pool for synthesis of adenosine-triphosphate. 

The GI absorption of the dmg after po adrninistration is slow and variable with estimates ranging from 20—55%. Once absorbed, 96% of the dmg is bound to plasma proteins and other tissues on the body. Whereas peak plasma concentrations may be achieved in 3—7 h, the onset of antiarrhythmic action may occur in 2—3 days or more. This may result, in part, from distribution to and concentration of the dmg in adipose tissue, Hver, spleen, and lungs. Therapeutic plasma concentrations are 1—2 p.g/mL, although there appears to be no correlation between plasma concentration and antiarrhythmic activity. The plasma half-life after discontinuation of the dmg varies from 13—103 days. The dmg is metabolized in the Hver and the principal metaboHte is desethylamiodarone. The primary route of elimination is through the bile. Less than 1% of the unchanged dmg is excreted in the urine. The dmg can also be eliminated in breast milk and through the skin (1,2). 

Hundreds of metabohc reac tions take place simultaneously in cells. There are branched and parallel pathways, and a single biochemical may participate in sever distinct reactions. Through mass action, concentration changes caused by one reac tion may effect the kinetics and equilibrium concentrations of another. In order to prevent accumulation of too much of a biochemical, the product or an intermediate in the pathway may slow the production of an enzyme or may inhibit the ac tivation of enzymes regulating the pathway. This is termed feedback control and is shown in Fig. 24-1. More complicated examples are known where two biochemicals ac t in concert to inhibit an enzyme. As accumulation of excessive amounts of a certain biochemical may be the key to economic success, creating mutant cultures with defective metabolic controls has great value to the produc tion of a given produc t. 

Bradycardia Bradycardia is a slow heart rate (60 beats per minute or slower) that does not meet the body s metabolic demands. Symptoms of bradycardia include dizziness, extreme fatigue, shortness of breath, or fainting spells. This can be compared to tachycardia, which is an extremely rapid heart rate, usually signified by a pulse of over 100 beats per minute. Adults usually have a resting heart rate of 70-80 beats per minute, although well-trained athletes can have resting rates in the 50 s or 60 s. Newborn babies have a normal heart rate of 120-160 beats per minute. A slowed heart rate can lead to a variety of other problems. First aid treatment may include administration of oxygen. 

The rate at which an absorbed chemical species is removed from the ASL determines whether reenirainment occurs during a breaching cycle,Slow removal rates relative to the breathing cycle allow the concentrations in the ASL to be higher than in the expiratory airstream. Figure 5.26 shows processes that diminish the ASL concentration of absorbed chemical species. Metabolic processes or interactions with ions and other chemically reactive substances found... 

Aromatic biguanides such as proguanil (181) have been found useful as antimalarial agents. Investigation of the metabolism of this class of drugs revealed that the active compound was in fact the triazine produced by oxidative cyclization onto the terminal alkyl group. The very rapid excretion of the active entity means that it cannot be used as such in therapy. Consequently, treatment usually consists in administration of either the metabolic precursor or, alternately, the triazine as some very insoluble salt to provide slow but continual release of drug. 

Human labor dominated all subsistence foraging activities, as the food acquired by gathering and hunting sufficed merely to maintain the essential metabolic functions and to support veiy slow population growth. Societies not very different from this ancestral archetype survived in some parts of the world (South Africa, Australia) well into the twentieth century Because they commanded veiy little energy beyond their subsistence food needs, they had very few material possessions and no permanent abodes. 

Divalent sulfur compounds are achiral, but trivalent sulfur compounds called sulfonium stilts (R3S+) can be chiral. Like phosphines, sulfonium salts undergo relatively slow inversion, so chiral sulfonium salts are configurationally stable and can be isolated. The best known example is the coenzyme 5-adenosylmethionine, the so-called biological methyl donor, which is involved in many metabolic pathways as a source of CH3 groups. (The S" in the name S-adenosylmethionine stands for sulfur and means that the adeno-syl group is attached to the sulfur atom of methionine.) The molecule has S stereochemistry at sulfur ana is configurationally stable for several days at room temperature. Jts R enantiomer is also known but has no biological activity. 

Protoanemonin, which has been isolated from Anemone pulsatilla and Ranunculus spp., was reported to inhibit root growth by slowing down metabolism and blocking mitosis 35). Erickson and Rosen 35) observed cytological effects in corn root tips at concentrations of 10M and lower. Cells undergoing division appeared to accumulate in the interphase or prophase stages. Metaphase, anaphase, and telophase stages were not observed. Cytoplasmic and vacuolar structures were disturbed and the presence of mitochondria could not be demonstrated in treated tissue. Thimann and Bonner 141) reported that protoanemonin was 10 to 30 times more inhibitory than coumarin in coleoptile and split pea stem tests, and that BAL prevented the inhibitory action. 

JV-Acetyltransferases (NATs) catalyze the conjugation of an acetyl group from acetyl-CoA on to an amine, hydrazine or hydroxylamine moiety of an aromatic compound. NATs are involved in a variety of phase II-diug metabolizing processes. There are two isozymes NAT I and NAT II, which possess different substrate specificity profiles. The genes encoding NAT I and NAT II are both multi-allelic. Especially for NAT II, genetic polymoiphisms have been shown to result in different phenotypes (e.g., fast and slow acetylators). 

DOX, as EPI seems to form fewer amounts of ROS and secondary alcohol metabolite, (ii) encapsulation of anthracyclines in uncoated or pegylated liposomes that ensure a good drug delivery to the tumor but not to the heart, (iii) conjugation of anthracyclines with chemical moieties that are selectively recognized by the tumor cells, (iv) coadministration of dexrazoxane, an iron chelator that diminishes the disturbances of iron metabolism and free radical formation in the heart, and (v) administration of anthracyclines by slow infusion rather than 5-10 min bolus (Table 1). Pharmacological interventions with antioxidants have also been considered, but the available clinical studies do not attest to an efficacy of this strategy. 

Type 2 diabetes is a heterogeneous and progressive endocrine disorder associated with insulin resistance (impaired insulin action) and defective function of the insulin-secreting (3-cells in the pancreatic islets of Langerhans. These endocrine disorders give rise to widespread metabolic disturbances epitomised by hyperglycaemia. The present classes of antidiabetic agents other than insulin act to either increase insulin secretion, improve insulin action, slow the rate of intestinal... 

Decreased activity of the thyroid gland results in hypothyroidism and, in severe cases, myxoedema. It is often of immunological origin and the manifestations are low metabolic rate, slow speech, lethargy, bradycardia, increased sensitivity to cold, and mental impairment. Myxoedema includes a characteristic thickening of the skin. Therapy of thyroid tumours is another cause of hypothyroidism. Thyroid deficiency... 

PPARy White adipose tissue, atherosclerotic lesions Insulin-sensitizing and glucoselowering re-directs TG from non-adipose tissues and visceral adipose depots for storage in subcutaneous adipose tissue slowed progression of atherosclerosis Fatty acids, eico-sanoids Th iazolid i ned iones pioglitazone (Actos ), rosiglita-zone (Avandia ) Type 2 diabetes, (insulin resistance, metabolic syndrome)... 

Edwards, R.H.T., Hill, D.K., Jones, D.A. (1975). Metabolic changes associated with the slowing of relaxation in fatigued mouse muscle. J. Physiol. 251,287-301. 

Histopathological examination shows the typical corelike lesions in a high proportion of muscle fibers in older patients this may amount to 100%. Most typically the cores are large and centrally-placed, but multiple cores may occur in the same fiber cross section. Most older patients show a striking predominance of type 1 (slow twitch oxidative) fibers and virtually all fibers with cores are type 1. Sometimes younger family members have more normal proportions of type 1 and type 2 fibers but, again, the cores are confined to the type 1 fibers. It is well established that muscle fiber types can interconvert due to altered physiological demands, and it is likely that fibers with cores convert to a basically slow twitch-oxidative metabolism to compensate for the fact that up to 50% of their cross sectional area may be devoid of mitochondria. 

AP -DDT is rather stable biochemically as well as chemically. Thus, it is markedly persistent in many species on account of its slow biotransformation. Metabolism of p,p -DDT is complex, and there is still some controversy about its specifics. The most important metabolic pathways are shown in Figure 5.2. 

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