3.8. Non-linear Kinetics
Most of these models assume that the adsorption and/or elimination of the drug is first order, and that a true first order rate constant and half life can be calculated. In reality any drug that is eliminated by other than passive diffusion will involve an energy intensive step, usually enzymatic, which is saturable at high concentrations. It is fortunate that most drugs are given at concentrations which are well below saturation levels, so that pseudo first order kinetics usually describe the situation well. However some drugs, for example phenytoin, salicylate, theophylline and probenecid, exhibit saturable kinetics in the therapeutic range, and this can have a profound effect on both levels and circulation times. In these cases Michaelis-Menten type kinetics must be invoked. The implications in adsorption and elimination of regular versus slow release formulations are large. A interesting example of a drug that is consumed at well above saturation levels is alcohol. It is eliminated from the body at an apparent zero-order rate equivalent to 12 oz of beer (equivalent to 8g of pure alcohol), (1 oz of liquor) per hour. At much lower levels a first order rate constant is obtained. This reflects the fact that alcohol is eliminated by enzyme mediated oxidative metabolism in the liver.
Situations in which nonlinear kinetics are observed include; drug absorption involving drugs with low solubility, slow dissolution rates saturable active absorption processes, rates influenced by fluctuating intestinal blood flow rates and changing pH and situations where drug binds to the gut wall, or food interferes with absorption; drug metabolism involving enzymatic reactions, alternate metabolic pathways and drug-drug interactions at the metabolic level; tissue binding by a saturable, or irreversible process, and drug/protein binding with displacement; and finally drug elimination by saturable excretory mechanisms, interference from other drugs or endogenous compounds, and altered renal function or GI motility due to pharmacological of physiological factors.