Describe the differences between linear pharmacokinetics and nonlinear pharmacokinetics.
Illustrate nonlinear pharmacokinetics with drug disposition examples.
Discuss some potential risks in dosing drugs that follow nonlinear kinetics.
Explain how to detect nonlinear kinetics using AUC-versus-doses plots.
Apply the appropriate equation and graphical methods, to calculate the Vmax and KM parameters after multiple dosing in a patient.
Describe the use of the Michaelis–Menten equation to simulate the elimination of a drug by a saturable enzymatic process.
Estimate the dose for a nonlinear drug such as phenytoin in multiple-dose regimens.
Describe chronopharmacokinetics, time-dependent pharmacokinetics, and its influence on drug disposition.
Describe how transporters may cause uneven drug distribution at cellular level; and understand that capacity-limited or concentration-dependent kinetics may occur at the local level within body organs.
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-dependent pharmacokinetics.
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 10-1, 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 10-1Examples of Drugs Showing Nonlinear Kinetics ||Download (.pdf) TABLE 10-1 Examples of Drugs Showing Nonlinear Kinetics
|Causea || ||Drug |
| ||Gl Absorption || |
|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 |
| ||Distribution || |
|Saturable plasma protein binding || ||Phenylbutazone, lidocaine, salicylic acid, ceftriaxone, diazoxide, phenytoin, warfarin, disopyramide |
|Cellular uptake || ||Methicillin (rabbit) |
|Tissue binding || ||Imiprimine (rat) |
|CSF transport || ||Benzylpenicillins |
|Saturable transport into or out of tissues || ||Methotrexate |
| ||Renal Elimination || |
|Active secretion || ||Mezlocillin, para-aminohippuric acid |
|Tubular reabsorption || ||Riboflavin, ascorbic acid, cephapirin |
|Change in urine pH || ||Salicylic acid, dextroamphetamine |
| ||Metabolism || |
|Saturable metabolism || ||Phenytoin, salicyclic acid, theophylline, valproic acidb |
|Cofactor or enzyme limitation || ||Acetaminophen, alcohol |
|Enzyme induction || ||Carbamazepine |
|Altered hepatic blood flow || ||Propranolol, verapamil |
|Metabolite inhibition || ||Diazepam |
| ||Biliary Excretion || |
|Biliary secretion || ||Iodipamide, sulfobromophthalein sodium |
|Enterohepatic recycling || ||Cimetidine, isotretinoin |