Adverse Drug Reactions - Part I
Course Number: 536
Course Contents
Pharmacokinetic Drug-drug Interactions
Duration and intensity of drug action in both target and non-target tissues is predicated on the drug’s plasma level and ability to reach intended and unintended receptors. In addition to dosage, the plasma level of a drug is modulated by the drug’s rate of absorption, distribution, metabolism, and clearance.6 These rates may be altered, i.e., induced or inhibited by concomitant drug therapy (Table 2). Some pharmacokinetic drug-drug interactions may at times be harnessed to optimize a drug’s therapeutic effect.
Table 2. Pharmacokinetic Drug-drug Interactions.
| Type | Examples of Mechanisms |
|---|---|
| Absorption | Drug A causes vasoconstriction at the site of administration and interferes with the systemic absorption of drug B administered at the same site |
| Drug A delays gastric emptying and the systemic absorption of drug B absorbed primarily in the intestine | |
| Drug A neutralizes gastric acid (elevates gastric pH) and prevents the absorption of drug B | |
| Drug A forms chelates or complexes with drug B and prevents its absorption | |
| Distribution | Drug A competes for plasma protein binding with drug B and increases its plasma level |
| Drug A blocks the transport of drug B into hepatocytes and increases its plasma level | |
| Drug A blocks the transport of drug B into the intestinal lumen and increases its plasma level | |
| Metabolism | Drug A induces a CYP450 isoenzyme responsible for the metabolism of drug B and decreases its plasma level |
| Drug A, inhibits a CYP450 isoenzyme responsible for the metabolism of drug B and increases its the plasma level | |
| Drug A inhibits CYP450-independent oxidation and causes accumulation of toxic intermediary metabolites of drug B | |
| Renal clearance | Drug A competes for renal tubular transport with drug B and increases its elimination half-life |
| Biliary clearance | Drug A increases the synthesis of biliary proteins involved in the conjugation of drug B and decreases its plasma level |
An example is the pharmacokinetic ADR between opioid analgesics and APAP. Opioids bind to μ-receptors in the gastrointestinal tract to increase the tone of the anterior portion of the stomach, decreases gastric motility, and delay the absorption of APAP, which takes place in the intestine.7 The historically cited example of the metronidazole inhibition of alcohol metabolism resulting in severe nausea and vomiting has recently drawn scrutiny and is no longer considered relevant.8