The pharmacokinetics of a drug after administration is usually defined by its absorption, distribution, metabolism and elimination, this process is commonly referred to as ADME.
Once a drug is administered, drug absorption begins; the process of transporting the drug from the site of administration to the systemic circulation.1
The most direct route of drug administration occurs via intravenous administration; drugs that are given by this route are said to have 100% bioavailability. In contrast, oral drugs are subject to absorption barriers in the gastrointestinal tract.1 The absorption of oral drugs is also governed by:1
- Absorptive surface area
- Transit time through the gastrointestinal tract
- Blood flow to the site of absorption
- Gastric and intestinal pH and subsequent pH dependent solubility2
- Intestinal efflux and influx transport (e.g. ATP binding cassette (ABC) gene products such as p-glycoprotein can impede the uptake of oral anticancer drugs)
- Intestinal metabolism (e.g. oral drugs are subject to intestinal metabolism by CYP3A4, a subclass of cytochrome p450 enzymes).
Following intravenous administration or absorption (in the case of oral kinase inhibitors), a drug distributes from the intravascular space to its target in the extravascular space.1 Most drugs bind to plasma proteins such as albumin. The amount of drug that moves to its target depends on how much drug binds to plasma proteins as only the free fraction of drugs is pharmacologically active.1
Uptake of drugs in the liver is mediated by either passive diffusion or active transport. Once in the liver, anticancer drugs undergo phase I and phase II metabolic reactions.1 Phase I reactions result in the loss of pharmacological activity or the activation of inactive prodrugs.1 Phase II reactions result in usually inactive derivatives for excretion; although this step is also needed to activate some (pro)drugs, such as capecitabine and tamoxifen, for example.1
The main routes of drug excretion are through the biliary tract and kidneys.1
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- Undevia SD, Gomez-Abuin G, Ratain MJ. Pharmacokinetic variability of anticancer agents. Nat Rev Cancer 2005; 5: 447-458.
- Budha NR, Frymoyer A, Smelick GS et al. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther 2012; 92: 203-213.