PMCOL 306 Administration, Absorption, Bioavailability

What is intra-arterial administration?

injection of drug into an artery to localize its effect in an organ

What is the definition of dose?

amount of drug administered (mols)

What is the definition of volume of distribution?

volume which a drug is distributed (L)

What is the definition of Concentration

Amount of drug in a give volume plasma (M)

What is the definition of absorption rate constant (Ka)?

rate at which a drug enters the body (h^-1)

What is the definition of elimination half-life (t_1/2)?

time it takes for the concentration of the drug to reach half the original value (h)

What is the definition of elimination rate constant? (k, k_e, k_el)

rate at which drug is removed from body (h^-1)

What is the definition of infusion rate? (k_in)

rate of infusion required to balance elimination (mol/h)

What is the definition of AUC?

area under the curve; integral of the concentration-time curve

What is the definition of clearance? (CL)

volume of plasma cleared of the drug per unit time (L/h)

What is the definition of bioavailability? (f)

fraction of drug that is systemically available

What is the definition of Bolus?

Single dose administered (usually intravascular).

What is the definition of Infusion?

Continuous administration

What is the definition of Extravascular and Intravascular?

Any route of administration besides intravascular (absorption rate and bioavailability become important factors) — Extravascular

Direct administration to blood pool (instantaneous absorption) — Intravascular

What is the definition of Dosing interval (Tau, τ)

Time between drug dose administrations (h)

What is the definition Cmax, Tmax, and Cmin

C_max — The peak plasma concentration of a drug after administration. (M)

T_max — Time to reach Cmax.(h)

C_min — The lowest (trough) concentration that a drug reaches prior to the next dose. (M)

What is the definition of Fluctuation (%PTF)

The ratio between Peak (Cmax) : trough (Cmin), within one dosing interval at steady state. (%)

What is Enteral vs. parenteral?

enteral - GI absorption
parenteral - everything else

What 3 administration routes are enteral and rank them in terms of onset effect?

oral (lowest) --> rectal --> sublingual (fastest)

What qualities effect the choice of administration? (5)

• physical drug propertie

  • (solid, liquid and gas)

• chemical drug properties

  • (solubility, stability, pH, logP [lipid solubility], irritancy)

• site of desired action

  • (local or generalized)

• effect of digestion and first-pass metabolism

  • Effects of digestive juices, extent of first pass metabolism, extent of absorption

• condition of patient

What are the 4 different routes of administration from the skin

• Transdermal (just below top layer of the skin)

• Intradermal (blow the skin in the dermis lay (2nd from the top))

• Subcutaneous (into fat)

• Intramuscular (into muscle)

What are some of the challenges of transdermal administration?

Hard from most drugs to pass through the outer most layer of skin — the stratum corneum

• stratum corneum is comprised of keratin-filled corneocytes which are anchored in a lipid matrix. This makes a brick and mortar making it hard from chemicals to pass through

How does a drug get absorbed when administered transdermally (3)? And what solutes would use each pathway (think chemical characteristics)

1. intracellular route

   • hydrophilic or polar solutes

2. intercellular route

   • lipophilic or non-polar solutes

3. transappendegeal route (passage of molecules through sweat glands and hair follicles)

   • high molecular weight molecules, charge molecules

What are some of the pros and cons of transdermal absorption

• Pros

  • Painless, non-invasive, easy to use

  • High bioavailability (bypass first pass metabolism)

• Cons

  • inefficient absorption (~1-2%), absorption depends of surface area and high logP

Would high lipophilicity increase or decrease transdermal adsorption?

increase

What are ways to enhance transdermal absorption? (3)

- abraded or burned skin (removed layers)
- suspended drug in oil to increase lipophilicity (oily vehicle)
- ion pairing (make neutral complex that can breakdown once in aqueous environment)

Intradermal Injection

• Drugs that would administered this way

• speed comparisons with subcutaneous

• Con

• Would be used to administer drugs that are unable to bypass the stratum corneum because of they are less lipophilic

• Faster onset affect (close to blood vesicles)

• Con - high skill need to hit the right layer

Subcutaneous

• Drugs that would administered this way

• Why a drug would be administered this way

• Use (rate of absorption)

• Cons (2)

• Pro

• non-ionic and high lipid solubility, non- irritant (in fat)

• drugs that have poor GI absorption are injected subcutaneously

• slow and constant rate of absorption (slow to leave fat cells and low blood flow to fat) cause sustained effect. (effect may be desirable — could implant solid pellet form of drug in fat — effect over months)

• Con

  • Drug can’t be an irritant causes pain, necrosis, inflammation

• Pro

  • cheep infusion compared to IV

  • Don’t need to me monitored my medical personal

Intramuscular

• Rate of absorption (2)

• Ways to influence absorption

• Sites of injection (good and bad)

• faster rate of absorption than subcutaneous or intradermal injections (because muscle is well vascularized)

• Oily drugs = slow constant absorption — aqueous drugs fast rapid absorption

• thinks ways to increase blood flow — Temperature, exercise, massage

• Site of injections

  • Dorsolateral (back of the butt)

    • Bad— lots of nerves and important blood vessels

  • Ventrogluteal (side of butt) — the best

    • Better because less likely to hit the important stuff

    • Women absorb in the butt slower because they have for fat there

  • Deltoid — the most common

    • Ideal place — accessible, faster than butt injections

Are injection administration routes subject to first-pass metabolism?

no

Sublingual (SL— under the tongue) and Buccal (cheek) administration

• Type of drugs

• Mechanism of absorption

• Consideration

• non-ionic and highly lipid soluble (most drugs can’t due to erratic absorption)

• absorbs in the month into the superior vena cava, by passing systemic circulation

• Eating, drinking, smoking can affect absorption

What are the advantages of rectal administration? (6)

- used in cases of nausea, vomiting, inability to swallow
- drugs that taste bad for kids
- rapid systemic effects
- absorption rate not affected by food
- can be easily removed/terminated upon adverse reactions
- some first-pass metabolism avoided (~50% not affected my first pass metabolism)

What are the disadvantages of rectal administration? (4)

- defecation can interrupt absorption process
- absorption can be highly irregular/incomplete
- reduced SA may limit drug absorption, ; low rectal fluids
- patient adherence

What is intrathecal administration?

direct injection into the brain or spinal subarachnoid space (bypass the BBB)

Can drugs administered intrathecally contain preservatives?

no; cannot contain ANY preservatives or potentially harmful ingredients

What are the advantages of pulmonary (lungs) absorption?

- almost instantaneous absorption of drug into blood (large SA in lungs)
- avoids first-pass metabolism

-Local appilcation of the drug

What are the advantages of intravenous administration?

- bioavailability is 100%
- drug delivery is accurate, controlled, and immediate (through titration)
- irritating drugs can be given (slowly bc of dilution)
- only way to administer high molecular weight drugs

-Can either give slow infusion or bolus injections

What type of drug must NEVER be administered intravenously?

What are some other disadvantages

drugs in oily vehicles (cause blood precipitates)

Increase risk of adverse effect — once the drug is injected can’t retreat

What is intra-arterial route of administration

Drug is injected directly into an artery to localize its effect in a particular tissue or organ

What are the advantages of intra-arterial administration?

- greater concentration of drug delivered to desired site
- chemotherapy drugs administered this way decrease systemic toxicity

What are the disadvantages of intra-arterial administration? (3)

- pharmacokinetics vary wildly
- dosages are different than intravenous administratoin
- technically challenging

• Need diagnostic agents for this route

What are the advantages of oral administration?

- pre-determined doses, portability, self-administration
- high patient compliance
- most convenient

What is the time of onset for oral administration?

30-90mins

When is absorption favoured for an oral drug?

when drug is in its non-ionized (more lipophilic) form

What are the disadvantages of oral administration?

- high first-pass metabolism
- drug must be stable in acidic environment

What is Lipinski's Rule of Five?

an orally active drug must not violate more than one:
- no more than 5 hydrogen bond donors (total number of N-H and O-H bonds)
- no more than 10 hydrogen bond acceptors (all N or O atoms)
- a molecular mass less than 500 daltons
- octanol-water partition coefficient (log P) that does not exceed 5

What does Lipinski's Rule of Five NOT predict?

it does no predict if a compound is pharmacologically active

Candidate drugs that conform to the Rule of Five tend to have lower what?

attrition rates (less fail) during trials

What percentage of orally administered drugs follow the Rule of Five?

50%

What does the Rule of Five assume?

assumes drugs are absorbed from the gut by passive diffusion (ignores membrane transporters)

What are some factors that affect absorption after oral admin? (6)

• ionization (pH) and lipid solubility

• Particle size and formulation

• Splanchnic Blood flow

• microbiota

• enzymes (CYP3D4)

• efflux pumps

What are the two major transporter classes?

ATP-binding casette (ABC) (efflux transporters) and solute carriers (SLC) (uptake transporters)

What does a negative logP value mean? Positive?

• LogP = log10 (partition coefficient)

• partition coefficient = [organic]/[aqueous]

negative - compound has higher affinity for aqueous phase
positive - compound has higher affinity for lipid phase

What is a consideration of having a drug with a high logP (highly lipophilic)

The drug will then intern have a low aqueous solubility which would compromise its bootability (won’t from into the blood).

The drug might be suck in fatty tissue and have toxic affects can occur

What logP value is ideal for dugs for the CNS, oral/intestinal absorption, sub-lingual

• CNS = 2

• oral/intestinal absorption, = 1.35-1.8

• sub-lingual = <5

When do drugs that are weak acids become ionized? Weak bases?

weak acid drugs ionize as pH increases (absorbed best in acidic environment)
weak base drugs ionize as pH decreases (absorbed best in basic environment)

Do non-ionized drugs or ionized drugs cross membranes?

non-ionized

How does the pH and pKa affect the absorption of a drug

• pH and pKa can affect drug absorption because the ionization state can affect whether a drug is absorbed

How do you calculate ionization ratio (base and acid)

pH that is given is likely to be an area of a body

Acid

• pka = pH + log [un-ionized]/[ionized]

Base

• pka = pH + log [ionized]/[un-ionized]

Look for the amount of drug drug that is in ionization form (if large amount of non-ionization form = good absorption)

What is oral bioavailability a product of

fraction absorbed (Fa)

Fraction escaping the gut wall (Fg)

Fraction escaping gut wall (Fh)

How do you calculate bioavailability

F= AUC_PO (oral admin) / AUC_IV

How do you calculate AUC_t-∞

AUC_t-∞ = C_{t (Concentration)}/ k (elimination rate constant)

Where in the body do you take a drug measurement from?

blood plasma

What percentage of the human body is water?

50-70%

What percentage of the human body is fat?

20%

What can drugs interact with in the blood

Drugs interact with protein, which prevents it from distributing to other compartments

What are 3 critical factors of drug distribution?

1) concentration gradient of free drug between blood and target organ

2) solubility of drug

3) blood flow to the target organ

Which 3 main compartments do drugs distribute into?

viscera (highly perfused), muscle (well perfused), fat (high lipid soluble drugs)

What are some barriers to drug distribution (6)

• pH

• Lipid partitioning

• Facilitative diffusion and active transporter

• Protein binds (either free form (active) or bond form)

• BBB

• Fat sequestration (getting suck in fat)

What are some details about protein binds and drug distribution

• Effect of plasma protein in drug

• How to overcome

• example

• Factors (3)

• Only the unbounded drug have any pharmacological effect

• Drugs that have extensive plasma protein binding will need a higher dose before having a therapeutic effect

• warfarin — 97% bound by protein, 3% is unbound

• Factors that impact

  • Concentration of drug in the body (more drug = more unbound)

  • Amount of plasma protein (liver disease, renal decrease plasma protein)

  • Drug-Drug interactions

    • competitive binding for plasma protein

Drugs and the BBB

• Why is it hard for drugs to enter (2)

• Hod do you calculate BBB permeability

• Methods of entering the BBB

• BBB have endothelial cells that are form by tight junction which limit the amount that can enter the brain

• basement membrane, pericytes, also contribute to the barrier

• logBB = AUC_brain/ AUC_plasma

• Ways to enter

  • Paracellular aqueous transport

  • Transcellular

  • Efflux pump blocker

  • receptors mediated transport

  • magnetitic field mediated

  • BBB distribution

What plasma proteins commonly bind to drugs?

albumin, alpha-1-acid glycoprotein, lipoproteins

What drugs bind to albumin? What drugs bind to alpha-1-glycoprotein? Lipoprotein?

acidic drugs - albumin
basic drugs - alpha-1-glycoprotein
after albumin and alpha-1-gP are bound --> lipoprotein

If a drug is evenly distributed throughout the body, the _________ will be equal to the ___________.

AVD (apparent volume of distribution), total body water

If a drug has a low AVD, where is majority of the drug?

plasma

If a drug has a AVD around 40 L, what does that mean?

about evenly distributed (lipophilic enough to enter cells but hydrophilic enough to remain in plasma)

If AVD exceeds 40L, what does that mean?

drug has concentrated into tissues

What is ka, ke, km, t1/2, k12, k21, k10?

ka - rate of absorption

ke - rate of elimination

km - rate of metabolism

t1/2 - drug half-life

k12 - distribution from central to peripheral

k21 - distribution from peripheral to central

K110- elimination of central compounds

What does a one compartment model of pharmacokinetic assume?

- drug distributed everywhere
- drug instantaneously and rapidly throughout the body

What is the difference between zero order and first order elimination kinetics?

zero order is a constant amount/time
first order is a constant fraction/time (most common)

What is V_c, V_ss, V_β

• VC (volume of central compartment) — The apparent volume of distribution immediately after a bolus (after injected)

• Vss (volume of distribution at steady state) — (the gradual increase of Vd)

• V_β (terminal elimination phase half-life) — what causes the constant line

What is the average amount of water in a man and woman

woman — 0.5 L/kg

Man — 0.6 L/kg

What can you tell when

• Vc < 3L

• Vc ~17L

• Vc ~ 40L

• Vc >40L

• Drug is unable to cross membrane

• When drugs bind to plasma more than tissue

• Vc < 3L

  • Drug is mostly in the plasma (heparin)

• Vc ~17L

  • Drug is mostly in extracellular water (mannitol)

• Vc ~ 40L

  • drug is distributed in the whole body (ethanol)

• Vc >40L

  • tissue binding exceeds plasma protein binding (chloroquine)

• Drug is unable to cross membrane

  • that means the Vc cannot be greater the extracellular space

• When drugs bind to plasma more than tissue

  • Vc would be smaller than 40L

What are some factors that affect AVD (other than drugs)

• Kidney or liver dysfunction

  • Would have an increase AVD with liver and kidney dysfunction because plasma binding is lowered

• Dehydration

  • Decrease water = decreased AVD

• Obesity

  • They would have a longer AVD. Because of the higher amount of fat cells highly lipophilic drugs would have longer half-lives and have to consider drug accumulation

• Age

  • Body fat increases and total body water decreases as we age. increase their elimination half life

Why is most drug data ln?

Most drug data shows a exponential decay curve. Which is why the data is most likely to be curved.

How do you calculate one-compartment IV bolus administration

D_B=V_DC_P

Why is estimation of elimination rate constant and half-life are important

1. the time to reach steady-state

2. the lime required to eliminate all or a portion of drug from the body

3. the amount of drug accumulated in the body within a given dosing i interval

4. the appropriate dosing interval

IV - bolus administration (two compartments) describe how the dose travels through the body. (4 phases)

1) the drug in given and it stays in the concentration

2) drug diffuses to the other less perfused tissue and is eliminated from the central compartment

3) the volume of the two reaches EQ

4) The central concentration is less that the less perfused tissue be.

What is flip-flop kinetics

When estimating the oral administration it is assumed that ka > > > > than k.

If K > > > ka than you would fine the Ka and K to be flipped

What is the importance of AI and ADME

Drug development cost a lot of money and not all drugs are able to make it to market

Machine AI is being used to screen for potential toxicity, poor pharmacokinetic properties, biological activity (receptor affinity)