What are the pharmacokinetics of Cardizem (diltiazem)?

Pharmacokinetics of Cardizem (Diltiazem)

Diltiazem exhibits nonlinear pharmacokinetics with extensive first-pass metabolism, resulting in approximately 40% absolute bioavailability, a plasma elimination half-life of 3.0-4.5 hours for immediate-release formulations (5-8 hours for extended-release), and 70-80% protein binding. 1

Absorption

• Bioavailability: Approximately 40% due to extensive first-pass hepatic metabolism 1
• Time to peak plasma levels:
  • Immediate-release: Rapid absorption
  • Extended-release (Cardizem CD): Detectable within 2 hours, peak at 10-14 hours 1
• Food effect: High-fat meals do not significantly affect absorption of extended-release formulations 1
• Age-related changes: Reduced first-pass metabolism in elderly increases oral bioavailability 2

Distribution

• Protein binding: 70-80% bound to plasma proteins 1
• Volume of distribution:
  • After IV: 299-411 liters 3
  • Varies with formulation and patient factors
• Age considerations: Increased free drug levels in elderly due to decreased albumin 2

Metabolism

Diltiazem undergoes extensive hepatic metabolism via CYP3A4, producing active metabolites including desacetyldiltiazem (25-50% as potent as parent drug). 1

• Primary pathway: CYP3A4-mediated (diltiazem is both a substrate and moderate inhibitor) 4, 5
• Active metabolites:
  • Desacetyldiltiazem (DAD): Present at 10-20% of parent drug levels, 25-50% as potent 1
  • N-desmethyldiltiazem (MA): Lower concentrations, less clinically significant 3
• First-pass effect: Decreases with age and in hepatic impairment 2
• Hepatic impairment: 69% increase in bioavailability and prolonged half-life in cirrhosis 1

Elimination

• Half-life:
  • Immediate-release: 3.0-4.5 hours 1
  • Extended-release (Cardizem CD): 5-8 hours 1
  • IV formulation: 6.8-6.9 hours 3
  • Terminal half-life of total radioactivity: ~20 hours (includes metabolites) 1
• Routes: Only 2-4% excreted unchanged in urine; remainder via hepatic metabolism and biliary excretion 1
• Renal impairment: No significant pharmacokinetic changes in severe renal dysfunction 1

Nonlinear Kinetics

Critical clinical consideration: Diltiazem exhibits dose-dependent, nonlinear pharmacokinetics with disproportionate increases in drug exposure at higher doses. 1, 6

• Dose escalation effects:
  • 120 mg to 240 mg daily: 2.7-fold increase in AUC 1
  • 240 mg to 360 mg daily: 1.6-fold increase in AUC 1
  • Apparent oral clearance decreases 35-51% over 3-4 fold dose increases 6
• Mechanism: Saturation of first-pass metabolism at higher doses 6, 7
• Steady-state accumulation: 2.39-fold increase in AUC with repeated dosing compared to single dose 7

Age-Related Pharmacokinetic Changes

In elderly patients, diltiazem clearance depends primarily on hepatic blood flow (high extraction ratio drug), which decreases with age, necessitating dose adjustments. 2

• Decreased hepatic blood flow reduces clearance
• Increased bioavailability due to reduced first-pass metabolism
• Increased free drug fraction from decreased albumin binding
• Higher risk of adverse effects in heart failure or hepatic disease 2

Therapeutic Plasma Concentrations

• Target range: 50-200 ng/mL 1
• Pharmacodynamic relationship: Strong correlation between plasma concentration and heart rate reduction in atrial fibrillation 3
  • 79 ng/mL for 20% heart rate reduction
  • 172 ng/mL for 30% heart rate reduction
  • 294 ng/mL for 40% heart rate reduction

Critical Drug Interactions Affecting Pharmacokinetics

Diltiazem is a CYP3A4 substrate and moderate inhibitor, creating bidirectional interaction potential. 5, 1

• CYP3A4 inhibitors (increase diltiazem levels):
  • Cimetidine: 58% increase in peak levels, 53% increase in AUC 1
• CYP3A4 inducers (decrease diltiazem levels):
  • Rifampin: Lowers diltiazem to undetectable levels 1
• Diltiazem as inhibitor (increases levels of):
  • Simvastatin: 5-fold increase in AUC 1
  • Midazolam/triazolam: 3-4 fold increase in AUC 1
  • Cyclosporine: 15-48% dose reduction required 1