Drug excretion

Drug and/or drug metabolites excreted in urine, faeces or bile. Drug metabolites rendered polar (and water soluble) by phase II metabolism are not reabsorbed, thus excreted in the urine.

1. Glomerular filtration
2. Active tubular secretion
3. Passive reabsorption by diffusion across the tubular epithelium

1. Clearance (CL) is an expression of the elimination of a drug from the body.
2. CL is the volume of blood removed (or cleared) of drug per unit of time (e.g., L/hour or mL/minute)
3. CL is important as it helps determine the dosage rate needed to maintain a desired [D]plasma

CL of a drug can be broken down into renal (CLR), hepatic (CLH) or other elimination routes (CLO) or described as total clearance (CLT).

CL= Rate of Drug Elimination/ [Drug]plasma concentration Example- Rate of drug elimination= 20 mg/hour [D]plasma= 2 mg/L CL= (20 mg/hour)/ (2 mg/l)= 10 L/ hour

1. Rate of drug elimination increases as plasma drug concentration increases. This is First order kinetics.
2. Elimination mechanisms become saturated and reach Vmax, the maximal elimination rate. This then becomes Zero order kinetics.

The elimination rate follows Michaelis-Menten kinetics: Re= (Vmax x [Drug]plasma)/ (Km+ [Drug]plasma) where Vmax is the maximum rate of drug elimination, Km is the drug concentration at which the rate of elimination is ½ Vmax. [Drug]plasma is the drug concentration in plasma.

1. In zero-order kinetics, the rate of the reaction is independent of the concentration of the reactant. The reaction proceeds at a constant rate regardless of changes in the concentration of the reactant.
2. In first-order kinetics, the rate of the reaction is directly proportional to the concentration of the reactant. The rate of the reaction increases or decreases as the concentration of the reactant changes.

In a steady state, the rate of drug administration is equal to the rate of drug excretion. So if we bring the equation of Flow clearance CL= Rate of elimination (Re)/ [Drug]plasma We can calculate:- Dosage rate= [Drug]plasma x CL

Dosage rate= {[Drug]plasma in steady state} x CL 20 mg/L x 3L/hour= 60 mg/hour

if we were using a non-IV ROA, we would have to take into account the bioavailability (F) for that ROA for that drug:
Dosage Rate = ([Drug]PlasmaSS x CL) / F

1. Elimination t1/2 determines the time required for [Drug]Plasma to achieve [Drug]PlasmaSS (steady state)
2. Elimination t1/2 determines how much time is required for drug to be eliminated from body This is extremely useful when designing a therapeutic dosing regimen.

The elimination half-life (t1/2) depends only on the volume of distribution (Vd) and clearance. 0.693 is the logarithm of 2, and represents the exponential rate of elimination (assuming elimination is by first order kinetics). The equation to calculate it is:- t1/2= (0.693x Vd)/CL

t1/2 is 50% of steady state. Thus, 5t1/2 is equal to the steady state approximately. If the half life of elimination is 18 minutes, it would take 90 minutes to reach steady state.

It would take 5 t1/2 (half lives) to get the IV infusion to completely wash out.

The equation is t1/2= (0.693x Vd)/CL

1. Effects on Volume of Distribution (a) Aging (decrease in muscle mass) - decreases t1/2 (b) Obesity (increase in adipose tissue)- increase t1/2 (c)Pathologic fluid- increase t1/2
2. Effects on Clearance Cytochrome P450 reduces drug plasma concentrations, thus increasing CL. (a) Cytochrome P450 induction -decrease t1/2 (b) Cytochrome P450 inhibition- increase t1/2 Cardiac failure- increase t1/2 Hepatic failure- increase t1/2 Renal Failure- increase t1/2

1. Occurs freely for drugs with a MW of less than 20 000 (very few exceed this), provided they are not bound to large plasma proteins.
2. If a drug binds to a plasma protein, its concentration in the glomerular filtrate will be less than its total plasma concentration.

Certain substances, including drugs and their metabolites, are actively transported from the peritubular capillaries (blood surrounding the tubules) into the tubular lumen. Tubular secretion of drugs:

• Can concentrate drugs in the tubular fluid against an electrochemical gradient
• Is a saturable process, each carrier has a transport maximum for a particular drug
• Can secrete drugs that are highly protein-bound.

Substances from the tubular fluid are reabsorbed back into the peritubular capillaries, returning essential molecules (e.g., water, glucose, electrolytes) to the bloodstream.

1. Lipid solubility - drugs with high lipid solubility will be extensively reabsorbed and excreted slowly
2. Polarity - highly polar drugs will be excreted without reabsorption
3. Urinary flow rate - diuresis decreases reabsorption
4. Urinary pH - the degree of ionisation of weak acids and bases can strongly influence their reabsorption
5. Alkaline pH increases excretion of acids, acidic pH increases excretion of bases.