Nonlinear or dose-dependent pharmacokinetics is a phenomenon that occurs when the pharmacokinetic parameters of certain drugs deviate from linear pharmacokinetics at higher doses. These drugs do not follow the expected first-order kinetics, where the rate of drug elimination is directly proportional to the drug concentration. Instead, they exhibit a nonlinear relationship, which can be attributed to several factors.

Nonlinearity can arise due to the saturation of plasma protein-binding or carrier-mediated systems. The drug molecules outnumber the binding sites available in the body, leading to a higher unbound fraction of the drug, which can increase the drug's effects or toxicity.

Nonlinearity can also be caused by the saturation of the presystemic gut wall or hepatic metabolism, which can impact the drug's absorption into the bloodstream. The drug's solubility and the presence of carrier-mediated transport systems can also contribute to nonlinearity in drug absorption.

Nonlinear distribution can occur due to the saturation of binding sites on plasma proteins or tissue binding sites. When the binding sites are saturated, the drug cannot bind and distribute effectively, leading to a higher drug concentration in the blood.

Nonlinearity in metabolism may also result from capacity-limited metabolism due to enzyme and cofactor saturation. The body's capacity to metabolize the drug is limited, accumulating the drug in the body.

Finally, nonlinear renal excretion can occur due to saturation of active tubular secretion or reabsorption. This can alter the amount of drug excreted by the kidneys, leading to a buildup of the drug in the body.

Nonlinearity can be detected by determining steady-state plasma concentration and other pharmacokinetic parameters at different doses. These drugs have an area under the curve (AUC) that is non-proportional to the bioavailable drug amount.

For instance, a high concentration of phenylbutazone (Butazolidine), a nonsteroidal anti-inflammatory drug, causes a rise in the unbound drug fraction. This can increase the risk of adverse effects. Similarly, pathological changes like renal nephrotoxicity from aminoglycosides, a class of antibiotics, can alter renal drug excretion, accumulating the drug in the body. This highlights the importance of careful monitoring and dose adjustments for drugs exhibiting nonlinear pharmacokinetics. Because the relationship between dose and plasma concentration is non-proportional, incorrect dosing can significantly increase the risk of toxic outcomes, making individualized therapy essential to ensure patient safety.

In conclusion, understanding nonlinear pharmacokinetics is crucial for predicting the behavior of certain drugs at higher doses and mitigating potential risks associated with drug therapy.