Pharmacokinetics of drugs

Pharmacokinetics of drugs

Pharmacokinetics is the study of the actions of the drugs in the body over a defined period of time. It deals with the absorption, distribution, biotransformation and excretion of the drug. Pharmacokinetics is ‘what the body does to the drug’.

Importance of kinetic study

1. For arriving at the dosage regimen (dose amount and dosing interval)
2. For understanding the absorption, distribution, metabolism and excretion of drugs
3. For comparison of drug routes
4. For comparison of different formulations (bioequivalence)
5. As an essential part of any drug development study
6. For therapeutic drug monitoring

Important pharmacokinetic parameters

t_1/2, Cl_B, V_d, AUC are the some most widely used parameters, described below-

Half life (t_1/2)

Plasma half life or t_1/2 is the time taken for the plasma concentration to be reduced to half its original value.

1. Elimination half life (t_{1/2 β} ) – the half life calculated from the elimination curve (log dose in y axis vs time )
2. t_1/2 b = 0.693 / β ( elimination rate constant) (where β = slope of the curve x 2.303)
3. Longer the half life longer is the duration of action
4. At one t_1/2 – 50 % of drug is eliminated
5. At two t_1/2 – 75% of drug is eliminated (50 + 50% of remaining 50)
6. At three t_1/2 – 87.5% of drug is eliminated
7. At 4 t_1/2 – 93.75 % of drug is eliminated

AUC

AUC or Area Under the concentration time Curve is Calculated by the trapezoidal rule. it is Important in calculating bioavailability and other parameters.

Volume of Distribution (V_d)

• It is defined as the amount of body fluid containing the drug – an apparent not an accurate value – the drug to be equally distributed in the whole body fluid.
• V_d = dose given / conc. of the drug in plasma
• For a more accurate description,
  • V_{d area} = Dose / β x AUC for i.v. (or) Dose x F / β x AUC for non i.v.
• V_d is indicative of extent of drug penetration.
• More distribution – greater V_d
• Highly protein bound and tissue bound drugs have higher V_d
• Drugs with higher V_d preferred for treatment in remote sites – skin, bone , muscle, etc.

Clearance – (Cl)

Total body clearance (Cl_B) is an index of efficiency of drug elimination. it is defined as the volume of body fluid cleared of the drug per unit time. For a given drug by the given route, Cl and V_d are characteristic and help in dose determination

V _{d =} Cl / β

Models in pharmacokinetics

Linear vs Nonlinear drug elimination

• If rate of elimination proportional to plasma concentration
• linear or first order (constant fraction of the drug eliminated per unit time)
• occurs for most normal kinetic processes.
• If rate of elimination is constant irrespective of concentration —> nonlinear or zero order reaction (constant amount of the drug eliminated per unit time)
• Occurs in toxicity, saturable mechanisms of elimination,
• At very high dose, reaction changes from first order to zero order
• Conc. increases disproportionately with increase in dose

Compartmental models

• A mathematical description of processes based on the number of phases. One compartment or two-compartment or multi-compartment a concept of imaginary division of the body into number of compartments.  The compartments do not correlate to any physical or anatomical compartments
• A single compartment model consists of only one elimination phase. A two compartment model consists of a rapid distribution phase and a slow elimination phase 
• Usually, I compartment indicates blood and highly perfused tissues and II compartment indicates peripheral tissues. In rare cases a third compartment corresponding to a deeper tissue component.
• Elimination is only from central compartment
• Most drugs follow two compartment open models with first order processes of absorption and elimination