Clearance of enzymes

It is accepted that the kinetics of myocardial protein appearance in the circulation depends on infarct perfusion. Early reperfusion causes an earlier increase above the upper reference limit and an earlier and greater enzyme peak after reperfusion. However, once the peak has occurred, there is no difference in the time of clearance of enzymes. In addition, enhanced washout identifies whether an artery is patent or closed but cannot distinguish between nor-... 

It appears that chromium(III) is an essential trace element in mammalian metabolism and, together with insulin, is responsible for the clearance of glucose from the blood-stream. Tungsten too has been found to have a role in some enzymes converting CO2 into formic acid but, from the point of view of biological activity, the focus of interest in this group is unquestionably on molybdenum. 

Glycosydation AChE and BChE carry 3 and 9, respectively, N-glycosylation consensus sequences attaching carbohydrate residues to the core protein via asparagines. Different molecular forms of the enzymes in various tissues, show different number and composition of carbohydrate residues. N-glycosylation at all sites was shown to be important for effective biosynthesis, secretion and clearance of ChEs from the circulation. Altered patterns of AChE glycosylation have been observed in the brain and cerebrospinal fluid of Alzheimer s disease (AD) patients, with potential diagnostic value. 

Data from both in vivo and in vitro systems showed PbTx-3 to have an intermediate extraction ratio, indicating in vivo clearance of PbTx-3 was equally dependent upon liver blood flow and the activity of toxin-metabolizing enzymes. Studies on the effects of varying flow rates and metabolism on the total body clearance of PbTx-3 are planned. Finally, comparison of in vivo metabolism data to those derived from in vitro metabolism in isolated perfused livers and isolated hepatocytes suggested that in vitro systems accurately reflect in vivo metabolic processes and can be used to predict the toxicokinetic parameters of PbTx-3. 

Use of zileuton is uncommon due to the need for dosing four times a day, potential drug interactions, and the potential for hepatotoxicity with the resulting need for frequent monitoring of liver enzymes. In patients started on zileuton, serum alanine aminotransferase concentrations should be monitored before treatment begins, monthly for the first 3 months, every 2 to 3 months for the remainder of the first year, and then periodically thereafter for as long as the patient continues to receive the medication. Zileuton also inhibits the cytochrome P-450 (CYP) mixed function enzyme system and has been shown to decrease the clearance of theophylline, R-warfarin and propranolol.34... 

Treatment of distal intestinal obstruction syndrome (DIOS) consists of oral or nasogastric administration of polyethylene glycol electrolyte (PEG) solutions. Enemas may also be used to facilitate stool clearance. IV fluids are often required to correct dehydration due to vomiting or decreased oral intake. Re-evaluation of enzyme compliance and dosing is essential to prevent further episodes. Patients with recurrent symptoms may require daily PEG administration (Miralax ).5 Severe presentations of DIOS or initial meconium ileus may require surgical resection. 

Assess adherence to the prescribed regimen, including timing of inhaled medications with respect to airway clearance therapies and timing of enzymes and insulin with regard to meals. Is the patient taking any medications not prescribed by the CF center team ... 

Ritonavir is a potent inhibitor of cytochrome P450 enzyme 3A and is used to reduce clearance of other Pis. 

Oxidative drug metabolism is extremely complex and possibly the most poorly understood ADME property. Rapid metabolism is unacceptable for drug candidates, except for drugs whose metabolite is the active moiety, because it causes duration of action to be too short. Considerable work has focused on the liver enzyme CYP3A4, which is responsible for the metabolic clearance of approximately 50% of marketed drugs. Recent approaches used to model and understand drug metabolism include database matching, quantum mechanics, QSAR, and structure-based analyses. 

For competitive inhibition, the intrinsic clearance of a substrate by an inhibited enzyme can be described with the following equation ... 

Sometimes CYPs can also produce reactive metabolite species that, instead of undergoing the normal detoxification pathway, can act as irreversible CYP inhibitors, thus causing toxicity. Such reactive metabolites that cause CYP inactivation are called MBI and are described in Chapter 9. Mechanism-based enzyme inhibition is associated with irreversible or quasi-irreversible loss of enzyme function, requiring synthesis of new enzymes before activity is restored. The consequences of MBI could be auto-inhibition of the clearance of the inactivator itself or prolonged inhibition of the clearance of other drugs that are cleared by the same isozyme. There may also be serious immunotoxicological consequences if a reactive intermediate is covalently bound to the enzyme. Therefore, screening of new compounds for MBI is now a standard practice within the pharmaceutical industry. 

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