Zero order kinetics

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
References in periodicals archive ?
For several reasons, (5) there is no evidence on lowering ITRA doses: (a) it has an erratic gastrointestinal absorption and food composition and gastric pH might influence drug's bioavailability (cyclodextrin-containing formulations are preferred); (b) ITRA has non-linear PK, thus, dose reductions may lead to unpredictable serum levels (zero order kinetics is dependent on enzyme saturation).
The patch followed zero order kinetics and a flux of 183.07 ug/cm2.hr was obtained.
The formulation followed zero order kinetics with Super case II drug release mechanism.
The order of drug release from the matrix systems was described by using zero order kinetics or first orders kinetics.
From the results, it was observed that, all the formulations made with PEO followed zero order kinetics with higher regression values (r) and exhibited non-Fickian mechanism.
Release of the constant amount of drug in specific time points characterises zero order kinetics. The zero-order process indicates that the drug release mechanism is not dependent on the drug concentration [37,38].
This fact shows that the reactions exhibit 1 to zero order kinetics with respect to all diols indicating Michaelis-Menten kinetics.
TABLE I REGRESSION PARAMETERS FOR PSEUDO ZERO AND FIRST ORDER REACTIONS FOR LIGHTNESS COLOR PARAMETER IN A TUNA-VEGETABLE MIXTURE DURING HEATING Zero order Parameter Temperature ([degrees]C) 110 115 120 125 [k.sub.o] or ln([k.sub.o]) * 50.7 50.9 50.5 50.3 -k ([min.sup.-1]) 0.145 0.187 0.279 0.426 [R.sup.2] 0.983 0.983 0.997 0.997 First order Parameter Temperature ([degrees]C) 110 115 120 125 [k.sub.o] or ln([k.sub.o]) * 3.927 3.926 3.929 3.947 -k ([min.sup.-1]) 0.003 0.004 0.007 0.012 [R.sup.2] 0.972 0.985 0.997 0.997 * [k.sub.o] for zero order kinetics and ln([k.sub.o]) for first order kinetics.
To determine the rate constant of the zero order kinetics model, the normalized liner thickness (i.e., liner thickness at time t, that is measured inside the mill during the mill shut-down periods, divided by the initial liner thickness) versus operating time was drawn in a log-normal graph.
During the same adsorption experiments, removal of N[H.sub.4]-N from the water column appeared to be best represented by zero order kinetics, as the regression equation was linear to 0 mg [L.sup.-1] (figure 3B).
The mechanism for coalescence was related to the loss in weight of dispersing liquid during an initial zero order kinetics stage.
The order of drug release from matrix systems was described by using zero order kinetics or first orders kinetics.