Pharmacokinetic (II)

Learning Outcomes

1. Define pharmacokinetic parameters such as bioavailability, volume of distribution (Vd), clearance (Cl) and elimination half-life (t1/2) using the concept of one and two-compartment models.

2. Explain the correlation between Vd, t1/2 and Cl and factors influencing each one of them.

3. Explain first and zero order kinetics and their clinical significance.

4. Define bioequivalence and its clinical significance.

Bioavailability:

Bioavailability refers to the fraction or percentage of an administered dose of a drug that reaches the systemic circulation in an unchanged form. It is a measure of the rate and extent to which a drug is absorbed from its dosage form and becomes available at the site of action. Bioavailability determines the amount of drug that is pharmacologically active and can exert its desired therapeutic effects.

Bioavailability can be affected by various factors, including the route of administration, drug formulation, drug solubility, gastrointestinal factors (e.g., gastric emptying, intestinal transit time), metabolism during absorption (e.g., first-pass metabolism), and drug interactions. The bioavailability of an orally administered drug is often compared to that of an intravenous (IV) administration, which is considered to have 100% bioavailability since the drug is directly introduced into the systemic circulation.

Knowing the bioavailability of a drug is important for determining appropriate dosing regimens, estimating the onset of action, predicting drug interactions, and ensuring therapeutic efficacy and safety.

Clearance Rate:

Clearance rate refers to the volume of plasma cleared of a drug per unit of time. It represents the body’s ability to eliminate a drug and is a critical pharmacokinetic parameter used to determine the appropriate dosing regimen for a drug. Clearance rate is typically expressed in units of volume per unit of time (e.g., L/h or mL/min).

Clearance involves the processes of metabolism and excretion, primarily by the liver and kidneys. The liver clears drugs through metabolic reactions, while the kidneys eliminate drugs through renal excretion. Other organs, such as the lungs and intestines, may also contribute to drug clearance to a lesser extent.

Clearance rate can be affected by various factors, including hepatic blood flow, hepatic enzyme activity, renal function, protein binding, and genetic factors. Changes in clearance rate can significantly impact drug concentrations in the body and can influence drug efficacy, safety, and dosing requirements.

Understanding the clearance rate of a drug is crucial for determining appropriate dosing intervals, maintaining therapeutic drug levels, preventing drug accumulation or toxicity, and optimizing drug therapy in individuals with altered clearance due to factors such as organ dysfunction or drug-drug interactions.

Distribution

Volume of Distribution: basically tells you whether the drug concentration is naturally going to be higher in blood or tissues

• need to know this to identify drug dose to be given (if the drug has high Vd, it means it does not stay within the blood and gets easily absorbed into tissues, which is good for the immediate tissue but it needs to stay in the blood so that it can be passed on to other organs)

Elimination

Routes of elimination

1. Hepatic
2. Renal
3. Biliary

Total Body clearance: sum of individual clearance

Rate of Elimination

First order kinetics

• Rate of elimination is prop to the drug concentration

Zero order kinetics

• Rate of elimination is not dependant on drug concentration in the body

• Rate of elimination is constant

Half life

Time taken for dose of drug to become half of original

Steady state

• When we want the rate of administration = rate of elimination

• In order to maintain drug at therapeutic range to obtain therapeutic benefits

• But it takes time ⇒ for life threatening conditions, we give a loading dose to reach steady state faster

Phase I and II Reactions

• When kidneys cannot remove lipophilic drugs as they get reabsorbed back into body

• So liver converts them into hydrophilic/water soluble substances via Phase I and II reactions

Phase 1

making lipophilic drugs more hydrophilic

Phase II

if phase I is still not enough, then it can be further conjugated into polar conjugates via various methods

For example, one might consider the hypothetical drug foosporin. Suppose it has a long lifetime in the body, and only 10% of it is cleared from the blood each day by the liver and kidneys. Suppose also that the drug works best when the total amount in the body is exactly 1g. So, the maintenance dose of foosporin is 100 milligrams (100 mg) per day—just enough to offset the amount cleared.

Suppose a patient just started taking 100 mg of foosporin every day.

• On the first day, they’d have 100 mg in their system; their body would clear 10 mg, leaving 90 mg.

• On the second day, the patient would have 190 mg in total; their body would clear 19 mg, leaving 171 mg.

• On the third day, they’d be up to 271 mg total; their body would clear 27 mg, leaving 244 mg.

As one can see, it would take many days for the total amount of drug within the body to come close to 1 gram (1000 mg) and achieve its full therapeutic effect.

For a drug such as this, a doctor might prescribe a loading dose of one gram to be taken on the first day. That immediately gets the drug’s concentration in the body up to the therapeutically-useful level.

• First day: 1000 mg; the body clears 100 mg, leaving 900 mg.

• On the second day, the patient takes 100 mg, bringing the level back to 1000 mg; the body clears 100 mg overnight, still leaving 900 mg, and so forth.