enzyme induction


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therapeutic drug monitoring

Clinical pharmacology The regular measurement of serum levels of drugs requiring close 'titration' of doses in order to ensure that there are sufficient levels in the blood to be therapeutically effective, while avoiding potentially toxic excess; drug concentration in vivo is a function of multiple factors Common TDM drugs Carbamazepine, digoxin, gentamycin, procainamide, phenobarbital, phenytoin, theophylline, tobramycin, valproic acid, vancomycin
Therapeutic drug levels in vivo–factors involved
Patient compliance  Ingestion of drug in the doses prescribed
Bioavailability Access to circulation, interaction with cognate receptor(s); ionized and 'free', or bound to a carrier molecule, often albumin
Pharmacokinetics Drug equilibrium requires 4-6 half-lives of drug clearance (a period of time for1/2 of the drug to 'clear', either through metabolism or excretion, multiplied by 4-6); the drug is affected by
Interaction with foods or other drugs at the site of absorption, eg tetracycline binding to cations or chelation with binding resins, eg bile acid-binding cholestyramine that also sequesters warfarin, thyroxine and digitoxin or interactions of various drugs with each other, eg digitalis with quinidine resulting in a 3-fold ↓ in digitalis clearance
Absorption may be changed by GI hypermotility or large molecule size
Lipid solubility, which affects the volume of distribution; highly lipid-soluble substances have high affinity for adipose tissue and a low tendency to remain in the vascular compartment, see Volume of distribution.
Biotransformation, with 'first pass' elimination by hepatic metabolism, in which polar groups are introduced into relatively insoluble molecules by oxidation, reduction or hydrolysis; for elimination, lipid-soluble drugs require the 'solubility' steps of glucuronidation or sulfatation in the liver; water-soluble molecules are eliminated directly via the kidneys, weak acidic drugs are eliminated by active tubular secretion that may be altered by therapy with methotrexate, penicillin, probenecid, salicylates, phenylbutazone and thiazide diuretics
First order kinetics Drug elimination is proportional to its concentration
Zero order kinetics Drug elimination is independent of the drug's concentration
Physiological factors
Age Lower doses are required in both infants and the elderly, in the former because the metabolic machinery is not fully operational, in the latter because the machinery is decaying, with ↓ cardiac and renal function, enzyme activity, density of receptors on the cell surfaces and ↓ albumin, the major drug transporting molecule
Enzyme induction, which is involved in a drug's metabolism may reduce the drug's activity; enzyme-inducing drugs include barbiturates, carbamazepine, glutethimide, phenytoin, primidone, rifampicin
Enzyme inhibition, which is involved in drug metabolism, resulting in ↑ drug activity, prolonging the action of various drugs, including chloramphenicol, cimetidine, disulfiram (Antabuse), isoniazid, methyldopa, metronidazole, phenylbutazone and sulfonamides
Genetic factors play an as yet poorly defined role in therapeutic drug monitoring, as is the case of the poor ability of some racial groups to acetylate drugs
Concomitant disease, ie whether there are underlying conditions that may affect drug distribution or metabolism, eg renal disease with ↓ clearance and ↑ drug levels, or hepatic disease, in which there is ↓ albumin production and ↓ enzyme activity resulting in a functional ↑ in drug levels, due to ↓ availability of drug-carrying proteins

enzyme induction

the process in which a structural gene coding for an enzyme of a catabolic pathway is activated by the substrate of that pathway (or a derivative of that pathway) binding with a repressor. The substrate is an INDUCER, which inactivates the repressor, allowing TRANSCRIPTION to proceed and in turn production of the enzyme that will catalyse the metabolism of the substrate. see OPERON MODEL.
References in periodicals archive ?
This preincubation was necessary to ensure that enzyme activity measurements are not confounded by the enzyme induction status of the community at the time of sampling (e.g., Smith and Tiedje 1979, Dendooven and Anderson 1994).
We conducted all enzyme induction and activity assays at both native pH and at a pH level adjusted to that of the other soil.
Evaluation of enzyme induction at a cellular level by mRNA quantitation and molecular probes combined with advances in polymerase chain reaction technology, could help to develop our understanding of the mechanisms involved in xenobiotic metabolism in the elderly.
Kinetic analysis of the metabolism of benzo([alpha])pyrene to phenols, dihydriols and quinones by high pressure liquid chromatography compared to analysis by aryl hydrocarbon hydroxylase, and the effect of enzyme induction. Cancer Res 1975;35:3642-50.
Comparative responsiveness of hypothyroxinemia and hepatic enzyme induction in Long-Evans rats versus C57BL/6J mice exposed to TCDD-like and phenobarbital-like polychlorinated biphenyl congeners.
Danshen had no effect on CYP1A2 protein expression after fourteen day treatment and confirmed that Danshen did not produce CYP1A2 enzyme induction in Sprague Dawley rat.
Biomarkers of exposure versus biomarkers of hepatic enzyme induction. We explored the relationship between biomarkers of exposure and biomarkers of hepatic enzyme induction.
Yoshimasa N, Oshigashi H, Masuda S, Akira M, Yasujiro M, Yoshiyuki K, Toshihiko O, Masayoshi I, Koji U (2000) Redox Regulation of Gluthathione S-Transferase Induction by Benzyl Isothiocyanate: Correlation of Enzyme Induction with the Formation of Reactive.
Key words: green tea, neutral endopeptidase, angiotensin-converting enzyme, enzyme induction
The higher amount of dioxin-like PCBs present in lot 6024 gave rise to greater enzyme induction as measured by EROD and MROD.
Role of cytochrome P450 enzyme induction in the metabolic activation of benzo[c]phenanthrene in human cell lines and mouse epidermis.
Enzyme induction is a common biological mechanism to increase total enzymatic activity.