INDIVIDUAL VARIATION IN 1ST-PASS METABOLISM

Individual variation in pharmacokinetics has long been recognised. Thi s variability is extremely pronounced in drugs that undergo extensive first-pass metabolism. Drug concentrations obtained from individuals g iven the same dose could range several-fold, even in young healthy vol unteers. In addition to the liver, which is the major organ for drug a nd xenobiotic metabolism, the gut and the lung can contribute signific antly to variability in first-pass metabolism. Unfortunately, the cont ributions of the latter 2 organs are difficult to quantify because con ventional in vivo methods for quantifying first-pass metabolism are no t sufficiently specific. Drugs that are mainly eliminated by phase II metabolism (e.g. estrogens and progestogens, morphine, etc.) undergo s ignificant first-pass gut metabolism. This is because the gut is rich in conjugating enzymes. The role of the lung in first-pass metabolism is not clear, although it is quite avid in binding basic drugs such as lidocaine (lignocaine), propranolol, etc. Factors such as age, gender , disease states, enzyme induction and inhibition, genetic polymorphis m and food effects have been implicated in causing variability in phar macokinetics of drugs that undergo extensive first-pass metabolism. Of various factors considered, age and gender make the least evident con tributions, whereas genetic polymorphism, enzymatic changes due to ind uction or inhibition, and the effects of food are major contributors t o the variability in first-pass metabolism. These factors can easily c ause several-fold variations. Polymorphic disposition of imipramine an d propafenone, an increase in verapamil first-pass metabolism by rifam picin (rifampin), and the effects of food on propranolol, metoprolol a nd propafenone, are typical examples. Unfortunately, the contributions of these factors towards variability are unpredictable and tend to be drug-dependent. A change in steady-state clearance of a drug can some times be exacerbated when first-pass metabolism and systemic clearance of a drug are simultaneously altered. Therefore, an understanding of the source of variability is the key to the optimisation of therapy.