Drug Metabolism and Pharmacokinetics

Introduction to Drug Metabolism

The liver plays a primary role in drug metabolism through cytochrome P450 (CYP) enzymes, with CYP3A4 responsible for metabolizing more than 50% of all drugs, as stated by the European Society of Cardiology and the British Journal of Pharmacology 1, 2
Age-related decreases in CYP450-mediated phase I reactions (20-50%) can significantly impact drug metabolism, according to the European Heart Association 1

Hepatic clearance depends on the liver's metabolic capacity (enzyme activity), hepatic blood flow, and plasma protein binding, as stated by the European Heart Association 1
Drugs with high hepatic extraction ratios (e.g., propranolol, lidocaine, metoprolol) are rapidly metabolized, and their clearance depends primarily on hepatic blood flow, with extensive first-pass metabolism, as noted by the European Society of Cardiology 1
Drugs with low extraction ratios (e.g., warfarin) are slowly metabolized, with elimination dependent on hepatic metabolizing activity, according to the European Heart Association 1

Age-related changes include reduced liver mass (20-30%) and hepatic blood flow in older adults, which can impact drug metabolism, as stated by the European Heart Association 1
Decreased activity of gut wall transporters and first-pass metabolism can modify oral bioavailability, according to the European Society of Cardiology 1
Drug absorption is primarily governed by passive diffusion across biological membranes, with most drugs achieving full absorption despite age-related physiological changes that may delay the absorption process, as noted by the European Heart Journal 1

The volume of distribution (V/F) is a primary parameter that may vary with physiologic and pathologic conditions, and protein binding affects drug distribution, with examples such as metformin being negligibly bound to plasma proteins 2
Clearance is a primary pharmacokinetic parameter that allows clinicians to prescribe correct dosage regimens, including hepatic, renal, and other routes of elimination, with metformin being primarily eliminated via renal clearance 2
Bioavailability, the fraction of an administered dose that reaches systemic circulation, is a key pharmacokinetic parameter 3

Pharmacodynamics describes the relationship between drug concentration and pharmacologic effect, with the integration of pharmacokinetics and pharmacodynamics providing more clinically relevant relationships for optimizing drug therapy, according to the American Academy of Otolaryngology-Head and Neck Surgery 4
CYP450 enzyme inhibition or induction is a common mechanism for drug interactions, with clinical consequences depending on the pharmacological and toxic effects of both parent drug and metabolites, as reported in the British Journal of Pharmacology 2
The American Academy of Otolaryngology-Head and Neck Surgery recommends considering pharmacokinetic principles to optimize dosing, particularly for drugs with narrow therapeutic windows, with the goal of minimizing adverse effects 4

The European Heart Journal recommends considering age, sex, and comorbidities when predicting absorption 1
The American Journal of Respiratory and Critical Care Medicine recommends monitoring therapeutic drug levels for drugs with narrow therapeutic windows 5
The American Academy of Otolaryngology-Head and Neck Surgery states that pharmacokinetics describes what the body does to the drug, whereas pharmacodynamics describes what the drug does to the body, highlighting the importance of understanding the distinction between the two 4