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 or 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). It is of note that some pharmacokinetic drug-drug interactions may at times be harnessed to optimize a drug’s therapeutic effect.

Table 2. Pharmacokinetic Drug-drug Interactions.
TypeExamples of Mechanisms
AbsorptionDrug 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
DistributionDrug 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
MetabolismDrug 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 clearanceDrug A competes for renal tubular transport with drug B and increases its elimination half-life
Biliary clearanceDrug A increases the synthesis of biliary proteins involved in the conjugation of drug B and decreases its plasma level

Consider the pharmacokinetic ADR between opioid analgesics and APAP. The opioid by binging to μ-receptors in the gastrointestinal tract increases the tone of the anterior portion of the stomach, decreases gastric motility, and delays the absorption of APAP, which takes place in the intestine. Another example, which affects metabolism, is the interaction between metronidazole and alcohol. Metronidazole inhibits the oxidation of an intermediary toxic metabolite of alcohol and causes severe nausea and vomiting.