M1 L2 - ADME

Absorption

movement of a drug from the site of administration to the blood

Distribution

movement of a drug from blood to tissues

Metabolism (biotransformation)

conversion of a drug into a different chemical compound

Excretion

removal of a drug and its metabolites from the body

Parenteral

Medication not by oral route

Common routes of administration

• oral

• injection

• sublingual

• buccal

• inhalation

• rectal/vaginal suppositories

• topical (ear/eye drops, nasal, creams/ ointments)

Bioavailability

The percentage of an administered drug that reaches the systemic circulation

Factors affecting bioavailability

• drug-related factors:

  • route of administration:

    • IV – 100%

    • other routes – variable but less than 100%

  • physical properties of the drug (tabs, caps, acidic, alkaline)

  • food (ex: vit d need fat)

  • first pass metabolism

  • other drugs taken concurrently

• patient-related factors:

  • GI factors: e.g., intestinal motility, pH

  • individual variation: e.g., age, sex, race

  • pathological conditions: e.g., liver or renal disease

Before absorption

a drug must be released from its vehicles (excipients)

Vehicles (excipients)

Dictates rate of absorption

Where is the main site of absorption

GI

Factors affecting drug absorption

– lipid Solubility

– pH

– transit time

– enzymatic & chemical stability

– food

– dosage form

Which route of administration skips absroption step?

IV route

Lipid soluble drugs ___ cross cell membranes

CAN

• ionized (charges)- a polar environment

• harder absorption

Water soluble drugs ___ cross cell membranes

CANNOT

• unionized (uncharged)- nonpolar environment

• easy absorption

Most drugs are what?

weak acids or bases

Degree of ionization depends on

• pH of the environment (e.g. blood (neutral), stomach (acidic), intestine (alkaline), …)

• pKa of the drug (pH where a drug is 50% ionized and 50% unionized)

Acetylsalicylic acid (Aspirin) is an ex of a weak _____

acid

• release H+ from acid → ionized

Norepinephrine is an ex of a weak _____

base

• release H+ from base → unionized

Weak Acids & Bases Chart

Drug absorption Along the GI- Stomach

– first station the drug reaches where it disintegrates and dissolves

– some proportion of drugs are absorbed depending on the pKa

– better absorption for acidic drugs

Drug absorption Along the GI- Small intestine

– high permeability, large surface area, and high blood flow

– primary site for drug absorption

– better absorption for basic drugs

Drug absorption Along the GI- Large intestine

– low permeability and relatively small surface area

– poor site for drug absorption

– some drugs are absorbed because of the long transit period (24-48 hours)

– increased duration in this site = increased possible absorption

Distribution

Different drugs have variable rates & extent of distribution

• Along concentration gradient between blood & tissue (hight o low concentration)

• Distribution determines drug’s:

– onset of action

– intensity of action

– duration of action

Factors Affecting Drug Distribution

• Physiological factors:

  • blood concentration of the drug

  • cardiac output

  • organ vascularity & blood flow

  • capillary permeability

  • tissue perfusion

• Drug properties:

  • degree of ionization

  • lipid solubility

  • binding to plasma proteins & tissue

  • pH

Volume of Distribution (Vd)

The measure of the apparent space in the body available to contain the drug

Vd = total amount of drug in the body(dose)/ drug concentration in the plasma

L in 70 kg (or L/kg)

• Drug reservoirs:

  • plasma proteins

  • intracellular space

  • fat

  • bones

  • muscles

Body water content

• Intracellular fluids 64%

• Interstitial fluid 25%

• Plasma 8%

• Minor components 3%

Drug Distribution & Elimination

A. No elimination – the graph shows only a steep rise to a maximum followed by a plateau

B. A route of elimination is present – the graph shows a slow decay after a sharp rise to a maximum

C. Drug placed in the 1st compartment (blood) equilibrates rapidly with the 2nd compartment (extravascular volume) but no elimination – the amount of drug in “blood” declines exponentially to a new steady state

D. A more realistic combination of elimination mechanism and extravascular equilibration – the graph shows an early distribution phase followed by a slower elimination phase

In both (B) and (D) the volume of fluid remains constant because of a fluid input at the same rate as elimination

Results of metabolism

– bioactivation

– deactivation

– detoxification

Purpose of metabolism

– increased drug’s water-solubility →

– help elimination from the body

Sites of Drug Biotransformation

• LIVER (primary site (main organ, not only organ):

  • high concentration of metabolizing enzymes

  • high blood flow

  • receives blood from GI tract

• Other sites:

  • e.g., kidneys, intestine, lungs, skin

How many phases of drug metabolism is there

2

Phase 1 of drug metabolism

reactions add or unmask a functional group (hydrolysis (+h20), oxidation (+O), reduction (+H)) in order to change the due to be able to pass on to phase 2

Phase 2 of drug metabolism

reactions add a large water-soluble component to allow excretion by the kidney (now water soluble)

• glutathione conjugation

• suphation

• acetylation

• glucoronidation

Oxidation reactions

• add O2/ lose an electron

• via cytochrome P450 (CYPs) enzymes:

  • CYP3A4 metabolizes about 50% of used drugs

• non-cytochrome P450: e.g.,

  • alcohol ⏤ alcohol dehydrogenase → aldehyde

  • norepinephrine ⏤ monoamine oxidase → inactivation

Cytochrome P450 is made by what?

The liver

Hydrolysis

• add H2O

• eg. carboxyl esterases

Reduction

• add H/ gain an electron

• e.g., nitro group (-NO2) ⏤ nitroreductase → amino group (-NH2)

Conjugation reactions

adding a water-soluble moiety to phase 1 product → water-soluble → easy to excrete

Glucuronidation

• via UDP-glucuronosyltransferase (UGT)

• added molecule: Glucoronates

Sulfation

• via: Sulfotransferase (SULT)

• added molecule: Sulfates

Glutathione conjugation

• via: Glutathione transferase (GST)

• added molecule: Glutathiones

Acetylation

• via: N-Acetyl transferase (NAT)

• added molecule: Acetates

First Pass Metabolism

Inactivation of orally administered drugs before reaching the systemic circulation

When and where does First Pass Metabolism occur?

• before absorption – in the intestine

• after absorption – in the liver

What are the results of first pass metabolism?

↓ amount of active drug reaching the blood & site of action

How do you avoid first pass metabolism?

change route of administration e.g., IV – skin – mucosa –

Factors Affecting Biotransformation

• Intra-individual differences:

  • diseases: especially liver disease

  • drug-drug interactions (DDI)

  • diet

  • gut microbiota

• Inter-individual differences:

  • age

  • sex

  • genetic factors (fast vs slow metabolizers)

Routes of excretion

• KIDNEY (primary route)

• GI tract

• lungs

• body fluids:

  • sweat, saliva, milk

Renal Excretion

• Glomerular function:

  • filtration:

    • filtrate = plasma ⎼ plasma proteins

• Tubular function:

  • reabsorption:

    • water & useful materials → back to blood

  • secretion:

    • waste products → urine

What is excretion?

Filtrate - reabsorption + secretion

Drugs & Renal Excretion

• Drugs must be water soluble (ionized) to be excreted through the kidney

• Lipid soluble drugs can be reabsorbed back into the blood

• Some active transporters in the renal tubule move drugs from blood → urine → excreted (e.g., penicillin)

RBF

• renal blood flow (what enters the kidneys)

+/⎼ 1200 ml (20-25% of CO)

GFR

• Glomeral filtrate rate

• GFR = 125 ml/min

  • ↓ GFR → ↓ drug excretion (e.g., renal failure)

CO

• cardiac output (heart rate x stroke volume)

Effect of urine pH on drug excretion

• acidic urine → ↑ excretion of basic drugs (e.g., opioids)

• basic urine → ↑ excretion of acidic drugs (e.g., aspirin)

Penicillin & Active Secretion

• +/⎼ 80% of penicillin dose is cleared from the body within 3–4 hours after administration →

• ↓ concentration & effect

How an we solve Penicillin & Active Secretion

• combine penicillin with probenecid

  • it competitively blocks penicillin excretion

Methods of excretion though GI tract

• lack of absorption through the intestine:

  • drugs with low bioavailability

  • protein-bound drugs in the intestine

• excretion via bile:

  • drug or its metabolite →

  • excreted by hepatocytes into bile →

  • eliminated through GI in the feces

Enterohepatic cycle

the biological pathway where substances travel from the liver into the bile, pass into the intestines, and get reabsorbed back into the bloodstream to return to the liver

Other routes of excretion

Lungs: e.g., gases, alcohol

Sweat; e.g., opioids, amphetamines

Saliva: e.g., caffeine, theophylline

Milk: e.g., caffeine, nicotine, anticonvulsants (caution while breastfeeding)