Bioavailability

The fraction of unchanged drug reaching the systemic circulation in following administration by any route

Measure of both rate and extent of drug that reaches the general circulation from an administered dosage form.

Drug in dosage form A successful TherapyDesired Effect

Attain and maintain an adequatedrug concentration at active site

Excretion

Metabolism

Distribution

Absorption

Drug dissolved in GIT fluid

Ability of drug dosage form to release drug after administered to patient

MTC

MEC

time

Blood conc.

Solid Dosage Form Granules Fine particles

Disintegration Deaggregation

Very limited Limited Optimum dissolution dissolution dissolution

Drug is dissolved in

GIT fluid

Membrane

Absorption

Drug in blood

Sequence of event involved in the dissolution and absorption of a drug from tablet dosage form

Drug in Dosage Form

AUC oralBioavailability = X 100 %

AUC Injected

Drug injected

AUC injected

AUC Oral

Drug given orally

Drug administered

Blood Conc.

Time (hours)

Determination of the Bioavailability

Comparing plasma concentration of drug after particular route of administration with plasma drug level by injection

Blood Conc.

Time (hours)

Two 250 mg. Erythromycin Tablet No Film or Enteric Coating

Two 250 mg. Erythromycin Tablet Film Coated

Two 250 mg. Erythromycin Tablet Enteric Coated

Factor affecting Bioavailability :

I. Patient variableII. Pharmaceutical variableIII. Route of administration IV. Time of administration

I. Patient variable Anatomy and Physiology patient factors : 1. Anatomical factor : Stomach :

* Primary function is not absorbing membrane * Stomach content contact with epithelial cell 30’ – 2 hr provides weakly acidic drug absorption Small Intestine : Villi and microvilli optimum absorption

Large intestine : Absorption is not completely

2. Physiological factor : a. Membrane area of absorptive site :

* Stomach abs. of weakly acidic drug * Intestine optimum absorption

b. pH of GIT fluid : * Various pH of GIT fluid

# pH fraction of un/dissociated drug if the fraction of undiss. Absorption

* With meal pH , and will be slowly c. Gastric emptying time :

* Optimal absorption is in small intestine The rate of gastric emptying time influences

drug absorption * Acid/enzyme-labile drugdegradation Intact drug

d. Intestinal transit : * Longer the period time in small intestine absorption

bioavailability

* Motility contact availability

e. Degradation and metabolism in GIT / Gut wall metabolism- Susceptible to Acid/enzymatic degradation bioavailability

ex.: Pro-drug ; Clindamycin palmitate degraded

become Clindamycin bioavailability

f. Hepatic metabolism ; First pass effect bioavailability

Transport mechanism of drug across GI membrane

Water Water

Protein

Lipid

Membrane is phospholipid bilayer : • Protein – lipid lipoidal layer permeable to hydrophobic molecule• Pore 0,4 nm molecule size < 0,4 nm pore

molecule size >>>> passive diffusion

GIT Fluid GIT membrane Blood

Drug in solution Drug bring into systemic circulations

Partition Diffusion Partition

Drug absorption • Generally passive diffusion• Active transport ; Levodopa, Thiamin etc.• Ion paring ; Tetracycline

II. Pharmaceutical Variable

A. Physicochemical properties of drug

B. Manufacturing technique of drug

C. Drug dosage form

A. Physicochemical properties of drug :

* Particle size : Smaller greater surface area dissolution rate

* Solubility of drug : too hydrophilic

too lypophylic* Solvate formation ; hydrated, unhydrate form Ex.: Amoxcicillin unhydrate is easily dissolved in

water* Polymorphism ; amorphous, crystalline Crystalline form is easily dissolved in water* Complexation ; - excipient in dosage form

- natural component in GIT

* Salt form

* Wettability

Absorption

B. Manufacturing process : 1. The composition of the dosage form

For ex.: other material in formulation (adjuvant) - Lubricating agents;

* hydrophilic* hydrophobic agents diss.rate

- Disintegrating agents diss.rate

2. Manufacturing techniqueCompression force

C. Dosage form1. Solution :

- Disperse system- Absorption (rate and/or extend) fastest and complete- OOA rapid

2. Suspension / Emulsion* Aqueous solubility Require the dissolution of drug* Absorption < solution* OOA < solution

3. Powder- Dissolution process

- Particle size, solubility etc - Possibility absorption of drug onto inert material

- Absorption < solution

4. Capsule:

- Capsule shell- Hard gelatin caps. dissolve readily than soft capsule - Require dissolution process

- Particle size, solubility, absorpt. Onto inert material- Absorption < powder

5. Tablet :- The rate of absorption < powder disintegration, deaggregation and dissolution process

6. Coated tablet :- Sugar coated more easily soluble than film coated- Factor influencing rate of absorption = factor in tablet- Enteric coated tablet disintegrates in intestine alkaline media - Sublingual tablet placed under the tongue and will readily

absorbed by mucose membrane

7. Suppositories :- Vaginal Supp. : local effect- Rectal supp. : - local

- systemic

The dissolution rate of drugs (that resists to gastric acid ) is decline according to following sequence : Solution – suspension – powder – capsule – tablet – sugar coated – film coated – enteric coated – prolong action (sustained released tablet)

III. ROUTE OF ADMINISTRATION :

1. Oral : With or without first pass effect With a first-pass effect:

1. Metabolism in GI fluid and membrane : Various pH solution, enzymes, mucous etc.

2. Hepatic metabolism3. Excreted into the bile

drug plasma level Bioavailability

Without a first-pass effect : drug plasma level drug absorbed

2. Rectal :- first-pass effect partially avoided- local effect- absorption unpredictable

3. Parenteral1. Intravenous :

- No absorption process- Complete drug availability- Bioavailability 100%

2. Intramuscular- Drug from aqueous sol.absorbed > suspension- OOA will vary- Absorption into blood site of injection

4. Topical : Local effect5. Inhalation :

- Very large surface for absorption- Alveolar and vascular epithelial membrane are quite permeable rapidly absorption- Gaseous or volatile substances

RODA Bioavailability (%)

OralRectalParenteral I.V. I.M. S.C.TopicalInhalationTransdermal

5 to < 10030 to < 100

10075 to < 10075 to < 100-5 to < 10080 to < 100

time

Blood concentration

V

IVIIIII

I

TheophyllinI. Intravenous 0.5 grII. Rectum (enema) 0.5 grIII. Oral 0.5 grIV. Oral 0.3 grV. Rectal suppositoria 0.5 gr

IV. Time of administration :

Food can modify drug absorption through :

- Altering gastric emptying time

- Altering GIT secretion

- Competition on drug absorption

- Drug complexation

- GIT content viscosity

How to calculate Bioavailability of drug :

Comparing :

Drug blood concentration or

urinary drug excretion

From Any dosage form

With Intravenously administration

Bioavailaability is expressed on scala 1 – 100 %

Parameter determining Bioavailability :

- Area Under Curve ( AUC )

- Height of Peak ( b max )

- Time of Peak ( t max )

AUC = The amount of drug absorbed following administration at single dose of

drugb.max = Height of peak : the highest drug achieved after administrationt.max= Time of peak : the length of time necessary to achieved the highest drug blood concentration after administration