Pharmacokinetic drug-drug interactions: a detailed systematic review

Abstract

Drug interaction refers to a clinically significant change in a drug's effectiveness caused by the concurrent use of another substance, such as another medication, food, or herbal supplement. Pharmacokinetic interactions affect the absorption, distribution, metabolism, or excretion of a drug. Absorption can be influenced by factors like pH, gastric emptying, and interactions with ions, medications, and food ingredients. For instance, p-aminosalicylate with diphenhydramine can delay stomach emptying and absorption. Distribution involves the movement of drugs from the bloodstream to various tissues and organs. An example is the interaction between warfarin, an anticoagulant, and sulfonamides, antibiotics, which compete for binding sites on plasma albumin. Metabolism, primarily occurring in the liver, involves converting drugs into inactive, excretable metabolites. Phase 1 metabolism often involves the cytochrome P450 enzyme system, which can be induced or inhibited by various drugs and environmental toxins, altering drug metabolism over days or weeks. Excretion, the final phase, involves removing drugs and their metabolites from the body. This can be affected by transporters like P‐glycoprotein (Pgp) and Multidrug resistance-associated protein 2 (MRP2) on the canalicular membrane or OATP transport on the sinusoidal membrane. For example, quinidine inhibits digoxin's hepatic uptake, raising its concentration and toxicity risk. Similarly, verapamil inhibits P-gp, increasing cyclosporine levels and toxicity risk. Understanding these interactions is crucial for managing drug therapy effectively.