Pharmacokinetic Drug Interactions
Pharmacokinetic drug interactions occur when one drug alters the absorption, distribution, metabolism, or excretion (ADME) of another drug. These interactions change the plasma concentration of the affected (object) drug, which may increase toxicity or decrease therapeutic response. Understanding these interactions is essential for designing safe and effective dosage regimens in clinical practice.
Introduction
Drug interactions can be undesirable or, in some cases, beneficial. A classic beneficial example is the use of probenecid with penicillin to prolong its therapeutic levels. In any interaction, the drug whose effect is altered is called the object drug, while the drug that causes the interaction is the precipitant drug.
Pharmacokinetic interactions specifically affect the concentration of the object drug in the body, influencing both the intensity and duration of action.
Classification of Pharmacokinetic Drug Interactions
- Absorption interactions
- Distribution interactions
- Metabolism interactions
- Excretion interactions
1. Absorption Interactions
These interactions occur mainly in the gastrointestinal tract and affect the rate or extent of drug absorption. They may result in faster, slower, increased, or decreased absorption.
a) Changes in Gastrointestinal pH
Some drugs require an acidic environment for optimal absorption. Drugs like H2-blockers, PPIs, and antacids increase gastric pH, which can reduce the absorption of weakly acidic or pH-dependent drugs.
Example: Reduced absorption of ketoconazole and itraconazole due to decreased gastric acidity.
b) Chelation Interactions
Certain drugs form insoluble complexes with minerals, preventing absorption.
- Tetracyclines and fluoroquinolones form complexes with calcium, magnesium, and iron
- Penicillamine absorption is reduced by some antacids
This interaction can be avoided by maintaining a 2–3 hour dosing interval.
C) Altered Gastrointestinal Motility
Drugs that slow GI motility may increase absorption by prolonging drug contact time, while drugs that speed up motility may reduce absorption.
- Propantheline increases absorption of slow-release digoxin
- Metoclopramide decreases digoxin absorption by accelerating gastric emptying
2. Distribution Interactions
Distribution interactions occur when one drug alters the protein-binding characteristics of another. Many drugs bind to plasma proteins such as albumin or α-1-acid glycoprotein.
If two highly protein-bound drugs are administered together, they may compete for binding sites. This increases the free (active) fraction of the displaced drug, potentially causing toxicity.
Drugs commonly involved in protein-binding displacement:
- NSAIDs
- Phenylbutazone
- Salicylates
- Sulfonamides
Example: Warfarin displacement by phenylbutazone increases bleeding risk.
Distribution interactions are most clinically relevant when the object drug:
- Is >90% protein-bound
- Has a small volume of distribution
- Has a narrow therapeutic index
3. Metabolism Interactions
Metabolic interactions are among the most clinically significant. They occur primarily in the liver via cytochrome P450 (CYP450) enzymes.
a) Enzyme Induction
Some drugs increase hepatic enzyme activity, leading to increased metabolism and reduced plasma levels of the object drug.
Examples:
- Phenobarbital increases metabolism of warfarin
- Rifampicin induces CYP enzymes and reduces levels of many drugs
- Carbamazepine induces its own metabolism (auto-induction)
- Cigarette smoking increases the metabolism of theophylline
Consequences of enzyme induction:
- Reduced therapeutic effect
- Need for higher doses to maintain adequate plasma levels
- Possible increase in active metabolite formation
b) Enzyme Inhibition
Inhibitors decrease metabolism, leading to higher plasma concentration and prolonged drug action.
Examples:
- Isoniazid inhibits phenytoin metabolism
- Alcohol with disulfiram increases acetaldehyde accumulation
- Allopurinol inhibits xanthine oxidase
Enzyme inhibition is especially dangerous for drugs with a narrow therapeutic index (e.g., anticoagulants, antiepileptics, hypoglycemics).
Types of enzyme inhibition:
- Competitive inhibition – inhibitor competes with substrate
- Non-competitive inhibition – inhibitor binds to another enzyme site
- Product inhibition – metabolite inhibits further metabolism
4. Excretion Interactions
These interactions occur mainly in renal excretion and may involve:
- Changes in renal blood flow
- Competition for active tubular secretion
- Changes in urinary pH
- Altered renal tubular reabsorption
a) Alteration in Renal Blood Flow
NSAIDs reduce renal blood flow, decreasing lithium clearance and raising lithium levels.
b) Competition for Tubular Secretion
Probenecid competes with penicillin and methotrexate at active secretion sites, decreasing their renal clearance.
c) Alteration of Urinary pH
Antacids alkalinize urine and reduce excretion of weak bases like amphetamines.
Biliary Excretion Interactions
Some high molecular weight drugs are excreted via the bile. Inhibition of biliary transport proteins can increase plasma drug levels.
Examples:
- Quinidine inhibits P-gp and increases digoxin levels
- Probenecid reduces biliary excretion of SN-38 (irinotecan metabolite)
- Cyclosporine inhibits P-gp, increasing AUC of several anticancer drugs
Clinical Significance
Pharmacokinetic drug interactions may lead to:
- Toxicity due to drug accumulation
- Therapeutic failure due to subtherapeutic levels
- Need for dose adjustments or enhanced monitoring
- Altered duration of drug action
Therapeutic drug monitoring (TDM) becomes essential for narrow therapeutic index drugs like digoxin, phenytoin, warfarin, and aminoglycosides.
Detailed Notes:
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