Drug–drug interactions (DDIs) occur when one drug alters the pharmacokinetics or pharmacodynamics of another, producing clinically significant changes in efficacy or toxicity. The NP must understand both pharmacokinetic interactions (affecting ADME: absorption, distribution, metabolism, elimination) and pharmacodynamic interactions (affecting drug action at the receptor level). Cytochrome P450 (CYP450) system: The CYP450 enzyme superfamily in the liver (and intestinal wall) is responsible for Phase I metabolism (oxidation, reduction, hydrolysis) of approximately 75% of all medications. The most clinically important CYP enzymes are: - CYP3A4: metabolizes ~50% of all drugs (statins, calcium channel blockers, benzodiazepines, macrolide antibiotics, calcineurin inhibitors, most protease inhibitors) - CYP2D6: metabolizes ~25% of drugs (codeine → morphine, tamoxifen → endoxifen, many antidepressants, metoprolol, many antipsychotics) - CYP2C19: metabolizes PPIs, clopidogrel (→ active metabolite), some SSRIs, phenytoin - CYP2C9: metabolizes warfarin (S-warfarin), phenytoin, NSAIDs, sulfonylureas - CYP1A2: metabolizes theophylline, caffeine, clozapine, olanzapine Enzyme INHIBITION: A CYP inhibitor DECREASES the metabolism of substrate drugs, causing INCREASED plasma levels → toxicity. Inhibition occurs rapidly (within hours to days of adding the inhibitor). Examples: fluconazole (CYP2C9/3A4 inhibitor) + warfarin → markedly elevated...