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CHAPTER OBJECTIVES

  • Compare the difference between linear pharmacokinetics and nonlinear pharmacokinetics.

  • Explain why nonlinear pharmacokinetics occurs with enzyme mediated or drug carrier systems. Discuss potential risks in dosing drugs that follow nonlinear kinetics.

  • Demonstrate how to detect nonlinear kinetics using AUC-versus-doses plots.

  • Use 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.

INTRODUCTION

Previous chapters discussed linear pharmacokinetic models using first-order kinetics to describe the course of drug disposition and action. These linear pharmacokinetic models assumed that the pharmacokinetic parameters for a drug does not change when different doses or multiple doses of a drug are given to the patient. For some drugs, increased doses or chronic multiple doses can cause deviations from the linear pharmacokinetic profile observed with single low doses of the same drug. This nonlinear pharmacokinetic behavior is also termed dose-dependent pharmacokinetics/nonlinearity when it is related to dose, and time-dependent pharmacokinetics/nonlinearity when it is related to time.

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 18-1, various causes of nonlinear pharmacokinetic behavior are theoretically possible. In addition to drug 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 their own renal drug excretion. In addition, gallstone obstruction of the bile duct will alter biliary drug excretion. In these cases, the main pharmacokinetic outcome will be a change in the apparent elimination rate constant which will cause a change in the systemic exposure (AUC).

TABLE 18-1Examples of Drugs Showing Nonlinear Kinetics

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