5 Pharmacokinetics

Pharmacokinetics

answers the question “what does the body does to the drug?”

Absorption

The process of drug permeation to the biological barrier & transfer of drug into the systemic circulation

• Topical

• Intravenous

Absorption applies to ALL routes, except:

Passive Diffusion

MOST dominant process for drug absorption

Drug Diffusion

Rate of absorption is proportional to the drug concentration gradient across the carrier and the surface available for absorption at that site

Fick’s First Law

Drug Diffusion is governed by

Fick’s First Law

• relates the diffusive flux to the concentration under the assumption of steady-state

Fick’s Second Law

relates to un-steady state

Passive Diffusion

• NOT energy dependent

• ACROSS conc gradient

• NO carrier protein

• NOT saturable

Facilitated Transport

• NOT energy dependent

• ACROSS conc gradient

• HAS carrier protein

• YES saturable

• facilitates polar and large molecules

Lipid Diffusion

• also known as Transcellular Pathway

• Requirement: high degree of lipophilicity

Aqueous Diffusion

• also known as Paracelullar Pathway and Convective Transport

• Requirement: small sized, polar

<200 daltons

size of “small sized”:

• Vitamin B12 (carrier: Cbl transporting protein)

• Cephalexin (carrier: Olegopeptide TP)

Examples of Facilitated Transport

Cbl transporting protein

carrier of Vitamin B12

Olegopeptide Transporter Protein

carrier of Cephalexin

Active Transport

Fastest process for drug absorption

Active Transport

• YES energy dependent

• AGAINST conc gradient

• HAS carrier protein

• YES saturable

• Levodopa (carrier: L-AAT)

• 5-FU (carrier: pyrimidine TS)

Examples for Active Transport

L-AAT

carrier for Levodopa

pyrimidine transporter system

carrier for 5-FU

Convective Transport

• aka paracellular transport, bulk flow

• Drug is absorbed through pores (8-13 armstrong of SI)

• Generally passive, but more permeable to cationic

• Applicable: Small, polar

• Atenolol

• Furosemide

• H-2 Blockers

Examples of Convective Transport

Ion-Pair Transport

• Not applicable for passive diffusion, BUT as long as the drug is lipophilic

• Absorption of highly ionized compounds

• Organic cation + Organic anion → Neutral molecules(high lipophilicity)

• Doxorubicin + dextran sulfate

• Quaternary ammonium compounds + sulfonates

Examples of Ion-Pair Transport

Pinocytosis

• active transport, needs ATP

• Aka cell drinking, fluid-phase endocytosis, bulk-phase pinocytosis

• DOES NOT need to be in aqueous solution

• Vitamins ADEK,

• Vitamin B12

Examples of Pinocytosis

• pH & degree of dissociation

• Blood flow

• Surface area

• Presence of eflux pumps

• Gastric Emptying Rate

Factors affecting Drug Absorption

HA & B

• o   Weak acid: HA → (H+) + A-

• o   Weak base: BH+ → B + (H+)

  Which forms are absorbed?

↑absorption

↑ blood flow =_ absorption

↑absorption

↑ surface are =_ absorption

↓GER

GER of heavy meals

↑GER

GER of Solution

↓GER

GER of Anticholinergic

↓GER

GER of high osmotic pressure

↓GER

GER of depressed

↓GER

GER of left side, sypine

↓GER

GER of vigorous exercise

↓GER

GER of Hypothyroidism

↑GER

GER of Hyperthyroidism

↑GER

GER of Mild Exercise

↑GER

GER of Right side, standing

↑GER

GER of stressed

↑GER

GER of low osmotic pressure

↑GER

GER of Prokinetics

TRUE

TRUE OR FALSE

GET is inversely proportional to GER

Partition Coefficient

• Measure of drug distribution in a lipophilic – hydrophilic phase system, indicating its ability to penetrate biological membrane

• Ratio of unionized drug distributed between non-polar and polar phase

Distribution Coefficient

• Ratio of the sum of the concentration of ALL forms of the compound in each of the two phase

↑absorption

↑concentration gradient = __ absorption

↑absorption

↑surface area = __ absorption

↓absorption

↑thickness = __ absorption

More unionized

In the stomach (pH=1.2), Weak acid is

More ionized

In the stomach (pH=1.2), Weak base is

More ionized

In the Small Intestine (pH= 6-7.4), Weak acid is

Less ionized

In the Small Intestine (pH= 6-7.4), Weak base is

FALSE

ratio: it is the ratio of non-aqueous (oil) to aqueous (water)

TRUE OR FALSE

1. The partition coefficient P is usually defined as the ratio of solubility in the aqueous phase to that in the non-aqueous phase

TRUE

TRUE OR FALSE

2. The greater the value of logP, the higher the lipid solubility of the solute

FALSE

Ratio: non-aqueous is non-polar (lipophilic), it does not mix well with ionized (polar) solutes

TRUE OR FALSE

3. Ionized solutes will readily partition into the non-aqueous phase

Non-Polar

Which of the following forms is absorbable?

1. polar & non-polar

Lipophilic

Which of the following forms is absorbable?

2. Lipophilic & Hydrophilic

Uncharged

Which of the following forms is absorbable?

3. Charged & uncharged

Non-ionized

Which of the following forms is absorbable?

4. Ionized & Non-ionized

Hydrophobic

Which of the following forms is absorbable?

5. Hydrophobic & Hydrophilic

Pinocytosis

‘cell drinking”

Liphophilicity

High logP means High__

Efflux

P-glycoproteins are ABC transporters that are involved in drug