Drug clearance or Kinetics of Elimination

Time course of drug clearance that is absorption, distribution and elimination can be determined in mathematical terms. Such a determination is important and its clinical significance is:

- In understanding and planning drug regimes.
- In deciding drug dose schedules.
- In helping and supplementing to clinical monitoring and judgement.

In fact drug elimination or drug clearance is the sum total of metabolic inactivation and excretion. Clearance is the best measure of drug elimination. Drug clearance is the theoretical volume of plasma from which drug is completely removed in unit time. It is usually expressed as mi/mm.

For example, if drug clearance of verapamil is 1000 ml/min, it means that verapamil from 1000 ml of plasma is removed in one minute. Total body clearance is a total sum of all available routes of excretion of a drug

A drug may be completely eliminated by glomerular filtration (e.g. aminoglycosides) or tubular secretion (e.g. penicillin). So rate of renal drug clearance cannot exceed glomerular filtration rate (120 ml/min) in case of former and renal plasma flow (700 ml/min) in case of later.

However, a lipid soluble and diffusible drug is reabsorbed in the distal tubules in variable amount. This reabsorption process may decrease renal clearance to as low a level as 1 ml/min (rate of urine formation).

Kinetics of Clearance

1. first order (exponential) kinetics: In this case, the rate of elimination of a drug is directly proportional to its plasma concentration. It means that a constant fraction of the drug in the body disappears in unit time. These drugs have a constant plasma half-life (t½). Elimination of most drugs or drug clearance follows first order kinetics.

In this case, the processes involved in removing most drugs are non-saturable over the clinically obtained plasma concentrations. Further, in this system log-plasma concentration-time curve is linear and near complete (97%) clearance is expected by the end of 5 t½ intervals after a single dose of a drug.

2. Zero-order (linear) kinetics: In this system, rate of elimination of a drug or rate of drug clearance remains constant irrespective of its plasma concentration. It means constant amount of the drug is eliminated in unit time. This is also called dose-dependent elimination or saturation kinetics.

In these cases, the reacting enzyme is limited and gets saturated (rate-limiting step). In this type of elimination of a drug or drug clearance decreases with increase in its plasma concentration.

Further, the plasma t½ is not constant and there occurs increase in biological half-life with an increase in the dose of a drug. This will be associated with disproportionate increase in the plasma level of the drug. So to avoid adverse drug reactions the dose of the drugs which follow zero-order kinetics, should be increased carefully.

The elimination of certain drugs or drug clearance such as ethanol, oral propranolol, dicumarol is exponential with lower dosage level. However, their elimination becomes “zero-order”, when dose exceeds a certain clinical level and elimination mechanism gets saturated.

3. Plasma half-life (t½): It is also called elimination half-life or biological half-life. It is defined as the time taken for the circulating plasma concentration of a drug to fall by 50%, When elimination of a drug or drug clearance is exponential, plasma half-life is independent of dose, route of administration and its plasma concentration.

The duration of t½ is raised if drug is widely distributed in the body; highly protein bound; and follows enterohepatic circulation. Mostly t½ is indicative of duration of drug and helps in determining the dosage schedule. However, it is not always true as in case of:

- Biotransformation of a drug into active metabolite.
- Pathological conditions (renal or hepatic dysfunction).
- Hit and run drugs (e.g. reserpine, MAO inhibitors).
- Drugs which follow zero-order kinetics.

Steady State Level

When drug is given once, it follows the following phases:

a. Absorptive phase: There is a rise in plasma concentration.

b. Distribution phase: A rapid decline in plasma concentration.

c. Elimination phase: A steady decline in plasma concentration.

Most of the time, drug is given in a fixed dose at fixed intervals or given by infusion at a fixed rate. So on repeated administration, mean plasma concentration rises gradually. It depends on intake and drug clearance. Initially intake is higher than elimination. So there occurs continuous rise in mean plasma concentration during this period.

Subsequently intake of drug becomes equal to its elimination or drug clearance. At this stage, a steady state level of mean plasma concentration is reached. It is reached after 5 t½ in case of drugs which follow first order kinetics.

It means the time to reach steady state level is a function of t½ (5 t½) irrespective of the dose or dose interval. However, the steady level reached is a function of the dose and dose intervals and not of t½. So it will be higher, if dose is increased or the dose interval is decreased.

Keeping the total daily dose constant, if the dose interval is increased, the mean steady state level will remain the same but there will be wide fluctuations in plasma concentration which may lead to toxicity at peak concentration and loss of biological activity in trough periods.

[Source: Principles of Pharmacology for Dental Students]