INTRAVENOUS

BIOPHARMACEUTICS

One-Compartment Open Model: Intravenous Bolus Administration:


this model is a simplistic view of drug disposition in the body, which in reality is infinitely more complex than a single compartment. In the body, when a drug is given in the form of an IV bolus, the entire dose of drug enters the bloodstream immediately, and the drug absorption process is considered to be instantaneous. In most cases, the drug distributes via the circulatory system to potentially all the tissues in the body.

Distribution:

Drug distribution: means the reversible transfer of drug from one location to another within the body. The distribution of drugs in the body depends on: 1- their lipophilicity 2- protein binding. Low plasma binding or high tissue binding or high lipophilicity usually means an extensive tissue distribution.

In pharmacokinetics, the distribution is described by the parameter V, the apparent volume of distribution. At equilibrium, V will theoretically not be lower than 7 L in a 70-kg person, but it has no upper limit. The volume in which the drug is distributed is termed the apparent volume of distribution, V D. which assumes that the drug is uniformly distributed in the body. The V D is determined from the preinjected amount of the dose in the syringe and the plasma drug concentration resulting immediately after the dose is injected.

Drug distribution patterns:

Distribution can be thought of as following one of four types of patterns: 1-The drug may remain largely within the vascular system. Plasma substitutes such as dextran are an example of this type, but drugs which are strongly bound to plasma protein may also approach this pattern.

Drug distribution patterns (Cont.):

2- Some low molecular weight water soluble compounds such as ethanol and a few sulfonamides become uniformly distributed throughout the body water.


Drug distribution patterns (Cont.):
3- A few drugs are concentrated specifically in one or more tissues that may or may not be the site of action. Iodine is concentrated by the thyroid gland. The antimalarial drug chloroquine may be present in the liver at concentrations 1000 times those present in plasma.

Drug distribution patterns (Cont.):

4- Most drugs exhibit a non-uniform distribution in the body with variations that are largely determined by the ability to pass through membranes and their lipid/water solubility. The highest concentrations are often present in the kidney, liver, and intestine usually reflecting the amount of drug being excreted.

Drug distribution patterns (Cont.):

Diagram Representing Various Volumes Distribution Patterns

Drug distribution patterns (Cont.):

Apparent volume of distribution ( V) is a useful indicator of the type of pattern that characterizes a particular drug. A value of V in the region of 3-5 liter (in an adult) would be compatible with pattern 1. This is approximately the volume of plasma. Pattern two would be expected to produce a V value of 30 to 50 liter, corresponding to total body water. Agents or drugs exhibiting pattern 3 would exhibit very large values of V. Chloroquine has a V value of approximately 115 L. Drugs following pattern 4 may have a V value within a wide range of values.

Drug distribution patterns (Cont.):

Volumes of body fluids
Fluid substances
Volume (liter)
Extracellular Fluid
19
Plasma
3
Interstitial fluids
16
Intracellular fluids
23
Total body water
42

Factors affecting drug distribution: 

Factors Affecting Distribution
A- Rate of distribution
B- Extent of Distribution
1. Membrane permeability 2. Blood perfusion
1. Lipid Solubility 2. pH – pKa 3. Plasma protein binding 4. Tissue drug binding

1.Membrane permeability: brain capillaries seem to have impermeable walls restricting the transfer of molecules from blood to brain tissue. Lipid soluble compounds can be readily transferred but the transfer of polar substances is severely restricted. This is the basis of the "blood-brain" barrier.

Factors affecting drug distribution (Cont.):

2. Blood perfusion rate: The rate at which blood perfuses to different organs varies widely:
Blood Perfusion Rate
Organ
Perfusion Rate(mL/min/mL of tissue)
Percentof cardiac output (CO)
Bone
0.02
5
Brain
0.5 - 0.55
14 - 15
Fat
0.01 - 0.03
2 - 4
Heart
0.6 - 0.7
4
Kidneys
4.0 - 4.5
22 - 24
Liver
0.8 - 0.95
25 - 27
Muscle
0.025 - 0.030
15
Skin
0.04 - 0.05
5 - 6

Factors affecting drug distribution (Cont.):

The rate at which a drug reaches different organs and tissues will depend on the blood flow to those regions. Equilibration is rapidly achieved with heart, lungs, liver, kidneys and brain where blood flow is high. Skin, bone, and depot fat equilibrate much more slowly.

Factors affecting drug distribution (Cont.):

B. Extent of Distribution 1.Lipid Solubility: Lipid solubility will affect the ability of the drug to bind to plasma proteins and to cross lipid membrane barriers. Very high lipid solubility can result in a drug partitioning into highly vascular lipid-rich areas. Subsequently these drugs slowly redistribute into body fat where they may remain for long periods of time.

Factors affecting drug distribution (Cont.):

2. Effects of pH:- The rate of movement of a drug out of circulation will depend on its degree of ionization and therefore its pKa. - Changes in pH occuring in disease may also affect drug distribution. For example, blood becomes more acidic if respiration is inadequate. 3.Plasma protein binding:- Extensive plasma protein binding will cause more drug to stay in the central blood compartment. Therefore drugs which bind strongly to plasma protein tend to have lower volumes of distribution. (↑ protein binding = ↓ V)

Albumin comprises 50 % of the total proteins binds the widest range of drugs. Acidic drugs commonly bind to albumin, while basic drugs often bind to α1-acid glycoproteins and lipoproteins. In order to achieve stable complexes, the initial electrostatic attraction is reinforced by van der Waal's forces and hydrogen bonding.

Factors affecting drug distribution (Cont.):

4. Tissue drug binding (tissue localization of drugs): In addition to plasma protein binding, drugs may bind to intracellular molecules. The affinity of a tissue for a drug may be due to: binding to tissue proteins or to nucleic acids, or in the case of adipose tissue, dissolution in the lipid material. e.g. The concentration of chloroquine in the liver is due to the binding of the drug to DNA. e.g. Barbiturates distribute extensively into adipose tissue, primarily because of their high lipid solubility. e.g. Tetracyclines bind to bone thus should be avoided in young children or discoloration of permanent teeth may occur.

A second pharmacokinetic parameter is the elimination rate constant, k, which governs the rate at which the drug concentration in the body declines over time. The one-compartment model that describes the distribution and elimination after an IV bolus dose is given in.The rate of elimination for most drugs from a tissue or from the body is a first-order process, in which the rate of elimination is dependent on the amount or concentration of drug present. The elimination rate constant, k, is a first-order elimination rate constant with units of time– 1 (eg, hr– 1 or 1/hr) K = Km + Ke

Calculation of Volume of Distribution

Significance of the Apparent Volume of Distribution
The apparent volume of distribution is not a true physiologic volume. Most drugs have an apparent volume of distribution smaller than, or equal to, the body mass. For some drugs, the volume of distribution may be several times the body mass and for a given dose, a very small C p 0 may occur in the body due to concentration of the drug in peripheral tissues and organs. For this dose, the small C p 0 will result in a large V D.


The apparent V D is a volume term that can be expressed as a simple volume or in terms of percent of body weight. In expressing the apparent V D in terms of percent body weight, a 1-L volume is assumed to be equal to the weight of 1 kg. For example, if the V D is 3500 mL for a subject weighing 70 kg, the V D expressed as percent of body weight is

Drug Clearance in the One-Compartment Model 

Clearance is refers to the volume of plasma fluid that is cleared of drug per unit time and measure of drug elimination from the body without identifying the mechanism or process. Drug elimination from the body is an ongoing process due to both metabolism and excretion through the kidney and other routes. The mechanisms of drug elimination are complex, but collectively drug elimination from the body may be quantitated using the concept of drug clearance.

The rate of drug elimination may be expressed in several ways

Drug Elimination Expressed as Amount Per Time Unit
For a zero-order elimination process, expressing the rate of drug elimination as mass per unit time is convenient because the rate is constant. In contrast For a first-order elimination process the rate is not constant and changes with respect to the drug concentration in the body. For a first-order elimination, drug clearance expressed as volume per unit time (eg, L/hr or mL/min) is convenient because it is a constant.

Drug Elimination Expressed as Volume Per Time Unit

Clearance is a concept that expresses "the rate of drug removal" in terms of volume of drug solution removed per unit time (at whatever drug concentration in the body prevailing at that time). the drug concentration in the body will gradually decline by a first-order process such that the mass of drug removed over time is not constant. The plasma volume in the healthy state is relatively constant because water lost through the kidney is rapidly replaced with fluid absorbed from the gastrointestinal tract.

Drug Elimination Expressed as Fraction Eliminated Per Time Unit

Consider a compartment volume, containing V D liters. If Cl is expressed in liters per minute (L/min), then the fraction of drug cleared per minute in the body is equal to Cl/V D.