Drug Absorption

PHCL 2XX

Dr VN NDIKUM
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Pharmacokinetic Overview (PK)

Pharmacokinetic Overview .
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Pharmacokinetic Overview .
Definition of PK:
The study of the movement of drugs in the body, including

the processes of absorption, distribution, localization in tissues, biotransformation and excretion. The actions of the body on the drug are called pharmacokinetic processes

Pharmacokinetic processes govern the absorption, distribution, metabolism and elimination of drugs Learning pharmacokinetics is of great practical importance in the choice and administration of a particular drug for a particular patient, e.g., one with impaired cardiac, hepatic or renal function

Drug Absorption
Absorption is the process by which a drug enters the bloodstream without being chemically altered, Or The movement of a drug from its site of application into the blood or lymphatic system.

NB: Absorption is instantaneous for bolus intravenous administration. Drugs taken by mouth pass to the stomach & then the intestine they are absorbed from the GItract into the circulatory system
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Most drugs cross biomembranes by passive diffusion where the rate of absorption is proportional to the drug concentration gradient. In which case will the rate be larger? A Out In B Out In
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The Movement of Drug Molecules Across Cell Barriers

Cell membranes form the barriers between aqueous compartments in the body. The most universal function of cell membrane is to act as a selective barrier to the passage of molecules, allowing some molecules to cross while excluding others. The cell membrane consists of a bimolecular lipid sheet (hydrophobic) interspersed with protein molecules (hydrophilic), and contains minute aqueous pores which allow passage of small hydrophilic substances.
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The Movement of Drug Molecules Across Cell Barriers

Cell membranes form the barriers between aqueous compartments in the body. The most universal function of cell membrane is to act as a selective barrier to the passage of molecules, allowing some molecules to cross while excluding others. The cell membrane consists of a bimolecular lipid sheet (hydrophobic) interspersed with protein molecules (hydrophilic), and contains minute aqueous pores which allow passage of small hydrophilic substances
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Factors which influence the rate of absorption

1. Mechanism of transportation across membrane 2. the physicochemical properties of the drug 3. routes of administration 4. dosage forms 5. circulation at the site of absorption 6. concentration of the drug
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Mechanisms of solute transport across membranes

passive diffusion filtration and bulk flow endocytosis active transport

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Mechanism of transportPassive diffusion

Passive diffusion is the direct movement of a solute through a biologic barrier from the phases of higher concentration to a phase of lower concentration. This is the most common mechanism of transport. The rate of diffusion is related to lipid solubility and polarity, pH, etc. The concentration gradient is the most important factor in determining rate. 13 Example include phenobarbital

Mechanism of transport- Filtration

Involves the bulk flow of water related to osmotic and hydrostatic pressures. Small water soluble, polar and non-polar, substances are transported by this process. It is most probable that these substance pass through spaces between cells rather than across the cell membrane. It is a purely physical process and the most important force is a pressure gradient. Examples include water and urea.
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Passive diffusion Aqueous diffusion Drug passes through aqueous pores in biomembranes BUT these pores limited to molecular wts of <40 Lipid Diffusion -drug if hydrophopic and uncharged dissolves in lipid (hydrophobic components) of biomembranes

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Mechanism of transport - Specialized Transport Mechanisms

1.

Facilitated diffusion or transport:

This is a carrier mediated transport system It is characterized by: Selectivity, Competitiveness, Saturability, Concentration gradient

2.

Active transport
is a carrier mediated transport system, energy is required and the transport is against a concentration gradient. is characterized by saturability, selectivity, and competitiveness.

3.

Pinocytosis
requires energy. The transport mechanism is by invagination of the cell membrane to form a vesicle and the engulfing of the invagination

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Mechanism

Direction

Energy required

Carrier

Satura ble

Passive Along gradient diffusion Facilitated Along gradient diffusion Active transport Against gradient

No

No

No

No

Yes

Yes

Yes

Yes

Yes

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Factors which influence the rate of absorption

Drug Absorption:

1. types of transport

2. the physicochemical properties of the drug

3. 4. 5. 6. routes of administration dosage forms circulation at the site of absorption concentration of the drug
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physicochemical factors of a drug that could influence transport

Following drug administration, there release of active drug from dosage form Disintegration and dissolution as critical steps in oral absorption Characteristics of the drug (solute) and the physicochemical factors influencing transport:

Molecular size and shape Lipid solubility Partition coefficient - relation to lipid solubility Weak acids - weak bases
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Lipid-Water Partition Coefficient (P.C

The ratio of the concentration of

the drug in two immiscible phases:

Phase 1: a nonpolar liquid or organic solvent (representing the membrane); and Phase 2: an aqueous buffer, pH 7.4 (representing the plasma)

The higher the lipid/water p.c. the

greater the rate of transfer across the membrane

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Factors which influence the rate of absorption

Drug Absorption:

1. types of transport 2. the physicochemical properties of the drug 3. routes of administration

4. dosage forms 5. circulation at the site of absorption 6. concentration of the drug

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Routes of Drug Administration

The route of administration (ROA) that is chosen may have a profound effect upon the speed and efficiency with which the drug acts

(see lecture on routes of administration)

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Factors which influence the rate of absorption

Drug Absorption:

1. types of transport 2. the physicochemical properties of the drug 3. routes of administration 4. dosage forms 5. circulation at the site of absorption
6. concentration of the drug
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Factors which influence the rate of absorption:

concentration of the drug

The concentration of a drug at the site of absorption could influence the rate of absorption The higher the concentration, the higher the rate of absorption Example:
Time-release preparations
Oral - controlled-release, timed-release, sustained-release designed to produce slow,uniform absorption for 8 hours or longer better compliance, maintain effect over night, eliminate extreme peaks and troughs parental administration (except IV), may be prolonged by

Depot or reservoir preparations

using insoluble salts or suspensions in non-aqueous vehicles.

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Factors which influence the rate of absorption

Drug Absorption:

1. types of transport 2. the physicochemical properties of the drug 3. routes of administration 4. dosage forms 5. circulation at the site of absorption 6. concentration of the drug
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Factors which influence the rate of absorption:

Dosage Form Form of preparation of administered

drug could also determine the rate of absorption. The rate of absorption will depend on the solubility and ease of dissolution of the drug

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Factors which influence the rate of absorption

Drug Absorption:

1. types of transport 2. the physicochemical properties of the drug 3. routes of administration 4. dosage forms 5. circulation at the site of absorption 6. concentration of the drug
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Factors which influence the rate of absorption:

Blood circulation at various organs The rate of absorption will also depend on the rate of blood flow in the organ where the drug is absorbed.

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Factors which influence the rate of absorption:

Blood circulation at various organs

Tissue Brain Heart Liver Kidneys Mass (kg) 1.4 0.3 2.9 0.3

Blood Flow (mL/min)

750 250 1500 1260

Flow (percent of Cardiac Output) 13.9 4.9 27.8 23.3

Skeletal muscle
Skin Placenta and fetal (term) Whole body

34.4
4.0 3.8 70

840
462 500 5400

15.6
8.6 9
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In summary
The Rate of Absorption is determined

by the physical characteristics of the drug, the speed which the drug is absorbed and/ or released, as well as the need to bypass hepatic metabolism and achieve high conc. at particular sites

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Absorption of Oral drugs

Destroyed in gut Not absorbed Destroyed by gut wall Destroyed by liver

Dose

to systemic circulation

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Absorption of inhaled products

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Absorption from the Skin

Must cross several cell layers (stratum corneum, epidermis, dermis) to reach blood vessels. Factors important here are: lipid solubility hydration of skin site (e.g. sole of feet vs. scrotum)
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Other Routes of Exposure

Intraperitoneal
large surface area, vascularized, first pass

effect.

Intramuscular, subcutaneous, intradermal:

absorption through endothelial pores into the

circulation; blood flow is most important + other factors

Intravenous

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Pharmacokinetic Parameters that are used to describe absorption

1. Bioavailability ( la biodisponibilit) F Describes Measures Rate and Extent of Drug Absorption into the Systemic Circulation 2. Tmax

3. Cmax

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Bioavailability (F):

Bioavailability (F):

Absolute Bioavailability:

the fraction of the dose that reaches the systemic circulation. (F=1 for IV administration.) Estimation of F for any other route in comparison to intravenous administration.
Estimation of F for a dosage form to another given by an extravascular (non-intravenous) route of administration.
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Relative Bioavailability:

Determinants of BIOAVAILABIITY
Affected by:
(eg: Lidocaine, propranolol) Solubility Instability (eg: Penicillin G, insulin)

Serum Concentration

1st pass metabolism

Injected Dose

Oral Dose

Time

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Area under the Curve (AUC)

AUC is a quantitative measurement of Bioavailability

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Bioavailability
The fraction of the dose of a drug (F) that enters the general circulatory system, F= amt. Of drug that enters systemic circul.
Dose administered

F = AUC/Dose

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 Examples:
If the drugs bioavailability is 50%, the body

will only absorb 250 mg of a 500 mg dose.

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Time to Peak Concentration (Tmax)

100 90 80 70 60 50 40 30 20 10 0 0 min 5 min 10 min 20 min 30 min 60 min

IV Oral Rectal

120 min

180 min

Question: Which route has the lowest Tmax?

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Maximum Concentration (Cmax)

100 90 80 70 60 50 40 30 20 10 0 0 min 5 min 10 min 20 min 30 min 60 min

IV Oral Rectal

120 min

180 min

Question: Which route has the Highest Cmax?

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 Cmax = maximal drug level obtained with the dose. Tmax = time at which Cmax occurs. Lag time = time from administration to appearance in blood. Onset of activity = time from administration to blood level reaching minimal effective concentration (MEC). Duration of action = time plasma concentration remains greater than MEC.

Plasma level curve

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