8.10 : Chronopharmacokinetics: Time-Dependent Pharmacokinetics

Chronopharmacokinetics studies the temporal change in drug absorption and elimination. These changes can be cyclical or non-cyclical. Cyclical changes occur over a regular interval, while non-cyclical changes occur over a longer, irregular period.

Time-dependent pharmacokinetics refers to non-cyclical changes in drug rate processes over a period of time. It can lead to nonlinear pharmacokinetics, where the relationship between drug concentration and time is not proportional. Non-cyclical changes in pharmacokinetics can result from alterations in organ physiology or biochemistry. For example, changes in enzyme activity or blood flow to specific organs can affect drug metabolism and clearance.

Time-dependent pharmacokinetics can also occur due to the autoinduction or autoinhibition of biotransformation enzymes. Autoinduction happens when repeated drug doses induce the enzymes responsible for drug elimination, increasing drug clearance. On the other hand, autoinhibition occurs when metabolites accumulate and inhibit the metabolism of the parent drug, resulting in decreased drug clearance.

Drugs that undergo time-dependent pharmacokinetics often exhibit variable clearance and elimination half-lives. This variability makes it crucial to consider the timing of drug administration to optimize therapeutic outcomes and minimize side effects. Some anticancer drugs, for example, are better tolerated when administered at specific times of the day. A study on the antimetabolite drug fluorouracil found that administering it in rodents during the morning resulted in the least toxicity.

Understanding the principles of chronopharmacokinetics and time-dependent pharmacokinetics is essential for tailoring drug regimens to individual patients and maximizing the efficacy and safety of drug therapy.