Module 1: Disposition of Drugs in Humans

Question 1

Pharmacokinetics

Answer 1

‘what the body does to the drug’

Defined as the measurement and
formal interpretation of changes with
time of drug concentrations in one or
more different regions of the body in
relation to dosing

Characterised by ADME, PK, and drug
disposition

Question 2

Absorption

Answer 2

The passage of a drug from its site of administration into blood

Defined by the term ‘bioavailability’, or the proportion of a drug dose that reaches the blood (or systemic circulation)

Calculated as AUC(non IV admin)/AUC (IV admin)

Question 3

Factors affecting drug absorption

Answer 3

• Drug disintegration/solubility (drug formulation)
• Drug physicochemical interactions with solvent/local components
• Drug physicochemical properties (affect drug diffusion, membrane permeability)
• Drug dose (in some cases)
• Permeability across the membrane barrier(s)
• Gut contents, GIT motility & splanchnic blood flow (for oral delivery)
• First pass metabolism and metabolism (oral)/degradation at site of administration
• Local blood/lymphatic flow rates (for eg. SC delivery, required to remove drug from the site)

Question 4

Distribution

Answer 4

the reversible transfer of a drug from one compartment of the body
into another

normally represented as a volume

Vc = Initial or ‘central’ volume of distribution
VDβ = volume of distribution during the terminal or ‘elimination’ phase of the plasma concentration-time profile

Question 5

Metabolism & elimination

Answer 5

Irreversible loss of drug from the body, either through drug metabolism (conversion of the drug to a metabolite) or excretion (in urine, faeces, sweat etc).

Question 6

Metabolism

Answer 6

Phase I – catabolic reactions often mediated by cytochrome
P450s

Phase II - anabolic or conjugation reactions (ie. Attachment of
a substituent group to make the metabolite/drug more polar 
facilitates more efficient urinary excretion)

Question 7

Excretion: Hepatobiliary

Answer 7

some drugs and drug metabolites are pumped from the liver into the bile duct, where they are passed into the intestines and excreted via the faeces

Question 8

Excretion - urinary

Answer 8

very small and polar drugs are filtered by the glomerulus in the kidneys and excreted into urine. Less polar drugs and drugs which are substrates for certain transport proteins in the proximal tubule can be reabsorbed back into blood.

Question 9

Excretion- exhalation

Answer 9

Volatile drugs such as isoflurane and other gas anaesthetics are eliminated in the breath via exhalation

Question 10

Key pharmacokinetic reasons for drug failure

Answer 10

• Low or variable drug bioavailability after oral or other delivery
• Rapid clearance from the body
• Distribution into ‘off-target’ organs/tissues
• Market failure as a result of the need for ‘invasive’ (eg. injections) dosing, where an existing less invasive (eg. oral) drug formulation is already available

Question 11

Solubility and Permeability

Answer 11

Ideally drugs should be highly soluble and highly permeable

High solubility = more drug in the tablet dissolves and is available
for absorption

High permeability = more of the dissolved drug passes from the intestines into blood

Question 11

Low or variable oral bioavailability

Answer 11

• Poorly water soluble drugs
• Poorly permeable drugs

Question 11

Rapid clearance or undesirable biodistribution profiles:

Answer 11

• Small molecule drugs
• Major problem in cancer chemotherapy

Question 11

A drug must be in solution for absorption to occur. Dictated by

Answer 11

• Solid state properties (crystallinity, salt form etc)
• Drug lipophilicity (Log P/polarity), ionisation (pH/pKa), H-bonding with
  solvent
• Properties of solvent (components in the gut. Eg. lipid soluble drugs
  dissolve better after eating fatty foods)

Question 12

A drug must be able to penetrate through the GIT to gain access to
blood. Dictated by:

Answer 12

• Lipophilicity, molecular weight, ionisation, H-bonding
• Substrates for transporters and metabolising enzymes in the gut or
  enterocytes

Question 13

Ideally want drugs with

Answer 13

MW <500 Da,
LogP (1-2),
H bond donors <5 and
H bond acceptors <10 in both ionized and un-ionized forms at physiological pH (2-8)

Question 14

Importance of protein binding in plasma

Answer 14

• Free drug is in equilibrium with bound drug (as free drug escapes from plasma, more drug is released from bound proteins)
• Variations in plasma protein levels (eg. in disease states) can significantly affect the drugs pharmacokinetics (and pharmacodynamics/toxicity)
• Extensive plasma protein binding can slow drug elimination from plasma
• Major drug binding protein is albumin, which has 2 high affinity drug binding sites per albumin molecule (albumin conc in plasma ~ 40 mg/ml – so VERY high)
• Can have competition between drugs in plasma for albumin binding which can therefore stimulate clinically relevant drug-drug interactions

Question 15

Major plasma binding proteins

Answer 15

Albumin
- 65 kDa. ~ 40 mg/ml
- Binds mainly acidic (anionic) drugs (eg. warfarin and ibuprofen)
- Levels decrease in pregnancy and renal failure

Alpha1-acidic glycoprotein
- 44 kDa, ~ 0.4 mg/ml
- Binds basic (cationic) drugs
- Levels increase after a heart attack

Lipoproteins
- 200-3400 kDa
- Varying concentrations in plasma
- Bind basic drugs

Question 16

Fu

Answer 16

Fraction of Unbound drug (Fu)

Fu = [D] / [D] + [DS]

Fu is INDEPENDENT of drug
concentration, since there are
usually more protein binding sites
than there are drug molecules

Can predict Fu using:
* The concentration of free drug [D]
* The affinity of the drug for the binding site
* The concentration of protein [S]

Question 17

What happens after drugs are absorbed?

Answer 17

inhaled and interstital = no first pass metabolism

oral = first pass metabolism

Question 18

Determinants of first pass metabolism

Answer 18

Can also be called Hepatic Clearance (CLH)

Hepatic blood flow (QH)
* Normally ~ 90L/h (vs blood flow through heart ~ 300 L/h)
* changes in certain disease states (eg. heart failure) and by the action of
certain drugs (eg. β-adrenoceptor antagonists)

Hepatic extraction ratio (EH)
* Fraction of unbound drug in plasma (fu)
* Intrinsic hepatic clearance (Clint) – the intrinsic ability of the liver to
remove (or metabolise) drug
* Hepatic blood flow (QH)

Question 19

Calculate hepatic extraction ratio (EH

Answer 19

Hepatic extraction ratio =
1 –
plasma concentration exiting the liver/
plasma concentration entering the liver

Values range from 0 (no drug is removed by the liver) to 1 (all drug is removed by the liver)

Hepatic extraction ratio =
Fu x Clint/
QH + (Fu x Clint)

Where….
Fu = fraction unbound drug
Clint = intrinsic hepatic clearance
QH = liver blood flow

Question 20

Intrinsic hepatic clearance =

Answer 20

Vmax/
Km

Where….
Vmax = the maximum rate at which
an enzyme can convert the drug to
a metabolite
Km = the Michaelis constant – expresses how tightly the enzyme binds to the drug (the lower the Km, the stronger the binding)

Question 21

Calculate first pass metabolism (hepatic Cl)

Answer 21

Hepatic clearance (ClH) = hepatic blood flow (QH) x hepatic extraction ratio (EH)

What can affect these parameters (ie. Change ClH?)

Answers:
* Liver fibrosis/damage
* Can reduce the metabolic capacity of liver
* Reduced liver blood flow
* Reduced albumin synthesis
* Drugs that compete with the same drug metabolising enzymes
* Exercise (can reduce hepatic blood flow by 70%)
* Infections (change plasma albumin concentration)