Drug Clearance Mechanisms

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Clearance - the volume of plasma cleared of drug by renal excretion/metabolism by other organs

  • Non-organ clearance of drugs include Hofmann elimination, ester hydrolysis (used to clear sux, atracurium, cisatracurium, mivacurium)
  • Almost all drugs at therapeutic dose ranges are cleared at a rate proportional to the amount of drug present in plasma (first-order kinetics)
  • More drug is cleared per unit time straight after dosing when plasma concentrations are the highest
  • A few drugs exceed metabolic/excretory capacity of the body even at therapeutic doses and a constant amount is cleared per unit of time (zero-order kinetics)
  • To maintain an unchanging plasma concentration with an infusion, infusion rate must be equal to the rate of drug clearance by hepatic and renal clearance mechanisms

Hepatic Clearance

  • The product of hepatic blood flow and hepatic extraction ratio
  • If hepatic extraction ratio is high (>0.7), drug clearance depends on hepatic blood flow - perfusion-dependent elimination
  • If hepatic extraction ratio is <0.3, only a small fraction of drug delivered to liver is removed per unit of time, and an excess of drug is available for hepatic-elimination mechanisms - changes in hepatic blood flow will not greatly influence hepatic clearance
  • Decrease in protein binding or increase in enzyme activity will greatly increase hepatic clearance of a drug with a low hepatic extraction ratio - capacity-dependent elimination

Biliary Excretion

  • Most metabolites of drugs produced in the liver are excreted in bile into the GI tract, and are often then reabsorbed from the GI tract into the circulation for elimination in the urine
  • Organic anions eg. glucuronides are transported actively into bile by carrier systems simliar to those that transport anions into renal tubules

Renal Clearance

  • Rate of elimination (mg/min) = Concentration (mg/mL) x Clearance (mL/min)
  • Clearance = Vd x K
  • Clearance = 0.693 x Vd / half-life
  • Clearance = Dose / AUC
  • Water-soluble compounds are excreted more efficiently by the kidneys than highly lipid-soluble compounds - metabolism of of lipid-soluble drugs to water-soluble metabolites for excretion is very important
  • The amount of drug entering the renal tubular lumen depends on the fraction of drug bound to protein and the GFR
  • Lipid-soluble drugs are the most easily reabsorbed from the tubules due to their ability to cross membranes easily
  • Production of less lipid-soluble metabolites promotes excretion into the urine
  • Rate or reabsorption from renal tubules is influenced by pH and rate of renal tubular urine flow
  • Weak acids are excreted more rapidly in an alkaline urine as more of the drug is ionized and cannot easily cross renal tubular epithelial cells