Non-Linear Pharmacokinetics PDF

Non-Linear Pharmacokinetics Objectives ● ● ● To understand dose-dependent pharmacokinetics. To learn about capacity limited kinetics. To know about the causes of non-linear Pharmacokinetic behaviour. ● Linear pharmacokinetic models assumed that the pharmacokinetic parameters for a drug would...

Non-Linear Pharmacokinetics Objectives ● ● ● To understand dose-dependent pharmacokinetics. To learn about capacity limited kinetics. To know about the causes of non-linear Pharmacokinetic behaviour. ● Linear pharmacokinetic models assumed that the pharmacokinetic parameters for a drug would not change when different doses or multiple doses of a drug were given. With some drugs increased doses or chronic medication can cause deviations from the linear pharmacokinetic profile observed with single low doses of the same drug. This non linear pharmacokinetic behaviour is Loading… ● ● ● ● also termed dose-dependent pharmacokinetics. Most of the processes of drug absorption, distribution, biotransformation and excretion involve enzymes or carrier-mediated systems. For same drugs given at therapeutic levels, one of these specialized processes may become saturated. ● ● ● In such cases, an essentially first-order kinetics transform into a mixture of first-order and zeroorder rate processes. Pharmacokinetic parameters change with the size of the administered dose. This dose dependent kinetics is referred to as nonlinear pharmacokinetics. Loading… Causes of Non-Linear Pharmacokinetic Behaviour ● ● ● 1. Due to a pathologic alteration in drug absorption, distribution and elimination For example, aminoglycosides may cause renal nephrotoxicity, thereby altering renal drug excretion. In addition, an obstruction of the bile duct due to the formation of gallstones will alter biliary excretion. ● ● ● 2. Saturation of enzymes and of the active transport systems for the drug. Drugs which show capacity limited elimination by the kidneys and capacity limited biotransformation exhibit non-linearity at high doses. Phenytoin, salicylates and theophylline are reported to exhibit capacity limited elimination whereas riboflavin is supposed ● ● ● ● ● to exhibit capacity limited absorption. 3.Changes in protein binding characteristics 4.Low solubilty of drug, erratic dissolution behaviour from dosage forms. 5. Variations in blood flow around the site of absorption. 6. Changes in pH at the site of absorption. Drugs which demonstrate saturation kinetics usually show the following characteristics: ● ● ● 1. Elimination of drug does not follow simple first-order kinetics, i.e. elimination kinetics are non-linear. The elimination half-life becomes greater as dose is increased. The AUC is not proportional to the amount of bioavailable drug. The saturation capacity-limited processes may be affected by other dugs that require ● ● ● ● the same enzyme or carrier-mediated system. The composition of the metabolites of a drug may be affected by a change in the dose. Since these drugs have a changing apparent elimination constant with larger doses, prediction of drug conc. in the blood based on a small dose is difficult. Drug conc. in the blood can increase rapidly once an elimination process is saturated. ● ● ● Metabolism (biotransformation) and active tubular secretion of drugs by the kidney are the processes most usually saturated. Following fig. shows plasma level-time curves for a drug that exhibits saturable kinetics. When a large dose is given, a curve is obtained with an initial slow elimination phase followed by a much more rapid elimination at lower blood concs. Loading… ● ● With a small dose of the drug apparent first-order kinetics are observed, since no saturation kinetics occur. In order to determine whether a drug is following dose-dependent kinetics, the drug is given at various dosage levels and a plasma level time curve is obtained for each dose. ● ● The curves should exhibit parallel slopes if the drug follows dose-independent kinetics. Alternatively, a plot of the areas under the plasma level-time curves at various doses should be linear. Michaelis-Menten Equations ● ● ● ● ● ● The elimination of drug by a saturable enzymatic process is described by Michaelis-Menten kinetics. If C is the conc. of drug in the plasma, then -dc VmC Elimination rate= ----------- = --------- (1) dt Km+ C Where C is the plasma conc. ● ● ● ● Vm is the max. rate of process Km is the Michaelis menten constant The value for Km is equal to the conc. at which the rate of process is half the max. rate Vm i.e. Vm Km = --------- (2) 2 ● ● The Michaelis-Menten eqn. is commonly used to describe the kinetics of in-vitro, in-situ as well as certain in-vivo processes that are known to be catalysed by enzymes. At low conc., where Km > C, Km+ C is approx. equal to Km -dc VmC ----------- = ----------- (3) dt Km ● ● ● ● As Vm / Km is a constant term, the eqn can be described as a first-order eqn. And Vm / Km is the first order elimination rate constant. At low plasma conc, first order kinetics is expected. Usually in most of the cases Km is larger than the plasma concs that are achieved. ● ● In some cases at higher doses C > Km then Km+ C is approx. equal to C. - dc VmC ----------- = ----------- = Vm (4) dt C Eqn 4 describes zero order kinetics. At high plasma conc. first order kinetics are not seen. ● ● ● When given in therapeutic doses, most drugs produce plasma drug concs well below the Km for all carrier mediated enzyme systems affecting the pharmacokinetics of the drug. Therefore, most drugs at normal therapeutic concs follow first-order rate processes. Only a few drugs such as salicylate and phenytoin tend to saturate the hepatic mixed function oxidases at higher therapeutic doses. ● ● With these drugs, elimination kinetics are firstorder with very small doses and mixed at higher doses And may approach zero-order with very high therapeutic doses. (Fig 8.3). Conclusion ● ● Drugs which show capacity limited elimination by the kidneys and capacity limited biotransformation exhibit nonlinearity at high doses. Pathologic alteration in drug absorption, distribution and elimination causes non linear behaviour.