The decline from peak plasma concentrations after drug administration results from drug elimination or removal by the body. The elimination of most drugs from the body involves the processes of both metabolism (biotransformation) and renal excretion (see Chapter 6). For many drugs, the principal site of metabolism is the liver. However, other tissues or organs, especially those tissues associated with portals of drug entry into the body, may also be involved in drug metabolism. These sites include the lung, skin, gastrointestinal mucosal cells, microbiological flora in the distal portion of the ileum, and large intestine. The kidney may also be involved in certain drug metabolism reactions.
Whether a change in drug elimination is more likely to be affected by renal disease, hepatic disease, or a drug–drug interaction may be predicted by measuring the fraction of the drug that is eliminated by either metabolism or excretion. Drugs that are highly metabolized (such as phenytoin, theophylline, and lidocaine) often demonstrate large intersubject variability in elimination half-lives and are dependent on the intrinsic activity of the biotransformation enzymes, which may vary by genetic and environmental factors. Intersubject variability in elimination half-lives is less for drugs that are eliminated primarily by renal drug excretion. Renal drug excretion is highly dependent on the glomerular filtration rate (GFR) and blood flow to the kidney. Since GFR is relatively constant among individuals with normal renal function, the elimination of drugs that are primarily excreted unchanged in the urine is also less variable.
The rate constant of elimination (k) is the sum of the first-order rate constant for metabolism (km) and the first-order rate constant for excretion (ke):
In practice, the excretion rate constant (ke) is easily evaluated for drugs that are primarily renally excreted. Nonrenal drug elimination is usually assumed to be due for the most part to hepatic metabolism, though metabolism or degradation can occur in any organ or tissue that contains metabolic enzymes or is in a degradative condition. Therefore, the rate constant for metabolism (km) is difficult to measure directly and is usually found from the difference between k and ke.
A drug may be biotransformed to several metabolites (metabolite A, metabolite B, metabolite C, etc); thus, the metabolism rate constant (km) is the sum of the rate constants for the formation of each metabolite:
The relationship in this equation assumes that the process of metabolism is first order and that the substrate (drug) concentration is very low. Drug concentrations at therapeutic plasma levels for most drugs are much lower than the Michaelis–Menten constant, KM, and do not saturate the enzymes involved in metabolism. Nonlinear Michaelis–Menten kinetics must be used when drug concentrations saturate metabolic enzymes (see also ...