Drug Clearance and Elimination Half-life

Factors influencing drug elimination

• Kidneys are the principle organ - renal filtration
• Drug metabolites rendered polar by phase II metabolism - can’t be reabsorbed by the renal tubules and so are excreted in urine

• Drug concentration changes over time in the body - absorption and elimination occur simultaneously

Clearance

• Clearance: an expression of the elimination of a drug from the body - the volume of blood removed of a drug per unit time

• Can be broken down into renal (CLR) , hepatic (CLH) or other (CHO elimination routes or described as total clearance (CLT)

• Helps determine the dosage rate needed to maintain a desired [D]plasma

• CL = rate of drug elimination/[D] plasma

First and zero order kinetics

• Initially, the rate of drug elimination increases as drug plasma concentration increases - first order kinetics (follows Michaelis-Menten kinetics)

• Over time, elimination mechanisms become saturated and reach VMAX – then becomes zero order kinetics

Steady state (SS)

• Exists when rate of drug administration (R0) = rate of elimination (RE)

• Dosage rate required to maintain steady state = [Drug]plasma X CL

Elimination half-life (t½)

• t½ = (0.693 x Vd)/CL

• Determines time required to reach SS and also time required for drug to be removed from body - usually 5 x t½ for either

• CL increases → t½ decreases
• Cytochrome P450 induction

• CL decreases → t½ increases
• Cytochrome P450 inhibition
• Cardiac/hepatic/renal failure

• Vd increases → t½ increases
• Pathological fluid
• Obesity (increased adipose tissue)

• Vd decreases → t½ decreases
• Aging (decreased muscle mass)