Previous chapters discussed linear pharmacokinetic models using simple first-order kinetics to describe the course of drug disposition and action. These linear 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 previously observed with single low doses of the same drug. This nonlinear pharmacokinetic behavior is also termed dose-dependentpharmacokinetics.
Many of the processes of drug absorption, distribution, biotransformation, and excretion involve enzymes or carrier-mediated systems. For some drugs given at therapeutic levels, one of these specialized processes may become saturated. As shown in Table 9-1, various causes of nonlinear pharmacokinetic behavior are theoretically possible. Besides saturation of plasma protein-binding or carrier-mediated systems, drugs may demonstrate nonlinear pharmacokinetics 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, gallstone obstruction of the bile duct will alter biliary drug excretion. In most cases, the main pharmacokinetic outcome is a change in the apparent elimination rate constant.
Table 9-1 Examples of Drugs Showing Nonlinear Kinetics ||Download (.pdf)
Table 9-1 Examples of Drugs Showing Nonlinear Kinetics
|Saturable transport in gut wall||Riboflavin, gebapentin, l-dopa, baclofen, ceftibuten|
|Intestinal metabolism||Salicylamide, propranolol|
|Drugs with low solubility in GI but relatively high dose||Chorothiazide, griseofulvin, danazol|
|Saturable gastric or GI decomposition||Penicillin G, omeprazole, saquinavir|
|Saturable plasma protein binding||Phenylbutazone, lidocaine, salicylic acid, ceftriaxone, diazoxide, phenytoin, warfarin, disopyramide|
|Cellular uptake||Methicillin (rabbit)|
|Tissue binding||Imiprimine (rat)|
|Saturable transport into or out of tissues||Methotrexate|
|Active secretion||Mezlocillin, para-aminohippuric acid|
|Tubular reabsorption||Riboflavin, ascorbic acid, cephapirin|
|Change in urine pH||Salicylic acid, dextroamphetamine|
|Saturable metabolism||Phenytoin, salicyclic acid, theophylline, valproic acidb|
|Cofactor or enzyme limitation||Acetaminophen, alcohol|
|Altered hepatic blood flow||Propranolol, verapamil|
|Biliary secretion||Iodipamide, sulfobromophthalein sodium|
|Enterohepatic recycling||Cimetidine, isotretinoin|
A number of drugs demonstrate saturation or capacity-limitedmetabolism in humans. Examples of these saturable metabolic processes include glycine conjugation of salicylate, sulfate conjugation of salicylamide, acetylation of p-aminobenzoic acid, and the elimination of phenytoin (Tozer et al, 1981). Drugs that demonstrate saturation kinetics usually show the following characteristics.
Elimination of drug does not follow simple first-order kinetics—that is, elimination kinetics are nonlinear.
The elimination half-life changes as dose is increased. Usually, the elimination half-life increases with increased dose due to saturation of an enzyme system. However, the elimination half-life might decrease due to “self”-induction of liver biotransformation enzymes, ...