Pharmacokinetics

Question 1

What are the two ways in which drug molecules move around the body?

Answer 1

1. Bulk flow (i.e. in the bloodstream, lymphatics or cerebrospinal fluid)
2. Diffusion (i.e. molecule by molecule, over short distances)

Question 2

Explain the relationship between rate of diffusion and molecular size

Answer 2

The rate of diffusion of a substance depends mainly on its molecular size, the diffusion coefficient being inversely proportional to the square root of molecular weight.

Consequently, while large molecules diffuse more slowly that small ones, the variation with molecular weight is modest

Question 3

State the permeability of the vascular endothelium in different tissues

Answer 3

Gaps between endothelial cells are packed with a loose matrix of proteins that act as filters

-Some regions, like blood-brain barrier of the CNS, and the placenta, have tight junctions between the cells and the endocytes encased in an impermeable layer of periendothelial cells

Other organs (e.g. spleen and liver) have an endothelium that is discontinuous allowing free passage between cells

Question 4

What are the different types of diffusion routes possible and which are used by drugs?

Answer 4

1. Diffusion through the lipid
2. Carrier-mediated transport
3. Diffusion through aquaporins - pore diameter is too small for most drug molecules
4. Pinocytosis - important for transport of some macromolecules but not for small molecules

First two are particularly important

Question 5

What factors affect Absorption?

Answer 5

• Routes of Administration
• Dosage forms
• Concentration of the drug
• The physicochemical properties of the drug
• Protein binding
• Types of transport
• Circulation at site of absorption

Question 6

What does the relative solubility (fat-soluble % and water-soluble %) depend on

Answer 6

1. pH of the drug
2. pH of the environment
3. pKa of the drug

Question 7

What are the effects of ionisation on drug absorption?

Answer 7

Non ionised drugs are absorbed better than ionised drugs
Drugs that are weak acids become highly ionised as pH increases (more basic). Drugs that are weak bases become highly ionised as pH decreases (more acidic)

Drugs become concentrated where they are most ionised as they can not cross the lipid bilayer

Question 8

What is the Henderson-Hasselbach equation?

Answer 8

pKa = pH + log10 ( [proton donor] / [proton acceptor])

Question 9

Why are the large gradients given by the Henderson -Hasselbach equation not realistic?

Answer 9

1. Assuming the total impermeability of the charged species is not realistic, and even a small permeability will attenuate considerably the concentration difference that can be reached
2. Body compartments rarely approach equilibrium

Question 10

Why does pH partition not the main determinant of the site of absorption of drugs from the gastrointestinal tract?

Answer 10

This is because the enormous absorptive surface area of the villi and microvilli in the ileum compared with the much smaller absorptive surface area in the stomach is of overriding importance

Question 11

What are the two types of transporters?

Answer 11

Transporters are broadly divided into SLC transporters and ATP-binding cassette (ABC) transporters.

The former facilitates passive movement of solutes down their electrochemical gradient, while the latter are active pumps fuelled by ATP

Question 12

What are the subtypes of SLC transporters?

Answer 12

• Organic cation transporters (OCTs) and organic anion transporters (OATs) -> typically operate purely passively
• Other SLCs are coupled to the electrochemical gradients of ions, generated by ATP-dependent ion pumps.

Question 13

Give an example of an ABC Transporter

Answer 13

P-glycoproteins belong to the ABC transporter superfamily and are responsible for multidrug resistance in cancer cells, many of which express an ATP-dependent pump with broad specificity called multidrug resistance protein 1 (mdr1)

Question 14

Give an example of the effects of polymorphic variation in genes coding carrier transporters

Answer 14

It contributes to individual genetic variation in responsiveness to different drugs, and competition between drugs for the same transporter cause drug–drug interactions

Ex.
Metformin acts partly through effects within hepatocytes. Single nucleotide polymorphisms (SNPs) that impair the function of OCT1 influence the effectiveness of metformin

Question 15

What factors limit the accumulation of drugs in body fat?

Answer 15

1. Fat represents a large, non-polar compartment. The effective fat: water partition coefficient is relatively low for most drugs
2. Its low blood supply. Drugs are delivered slowly to body fat, and the theoretical equilibrium distribution between fat and body water is delayed

Question 16

Define bioavailability

Answer 16

used to indicate the fraction (F) of an orally administered dose that reaches the systemic circulation as intact drug, taking into account both absorption and local metabolic degradation

Question 17

What is metabolism or biotransformation?

Answer 17

Conversion of one form of the drug into another form –> lipid-soluble drugs into water-soluble forms to enhance excretion

Question 18

What are the possible consequences of metabolism?

Answer 18

• Inactivation to produce inactive metabolites
• Production of an active metabolite from an inactive prodrug
• Production of an active metabolite from an active drug

Question 19

What is the Phase 1 reaction of metabolism?

Answer 19

They are catabolic: oxidation/reduction/hydrolysis

Introduces a reactive group into the molecule (known as functionalization). This group serves as the point of attack for conjugating systems to attach a substituent

Products are often more chemically reactive, and hence, paradoxically, sometimes more toxic or carcinogenic than the parent drug

Question 20

What is the Phase 2 reaction of metabolism?

Answer 20

They are catabolic and involve conjugation (i.e. attachment of a substituent group)

Results in inactive products

Possible chemical groups: glucuronyl, sulphate, methyl or acetyl

Question 21

What is first-pass metabolism?

Answer 21

Some drugs are extracted so efficiently by the liver or gut wall that the amount reaching the systemic circulation is considerably less than the amount absorbed

Reduces bioavailability

Question 22

Why it important to consider first-pass metabolism?

Answer 22

1. A much larger dose of the drug is needed when it is taken by mouth as opposed to parenterally
2. Marked individual variations occur in the extent of first-pass metabolism, both in activities of drug-metabolising enzymes and also as a result of variations in hepatic or intestinal blood flow

Question 23

How do CYP P450 enzymes work?

Answer 23

Mechanism involves a complex cycle, but the outcome of the reaction is the addition of atom of oxygen to the drug to form a hydroxylated product (DOH), the other atom of oxygen being converted to water

Question 24

Give examples of inhibition of CYP Enzymes

Answer 24

1. Compete for active sites but are not themselves substrates: quinidine (inhibits CYP2D6
2. Non-competitive inhibitor: Ketoconazole (forms a tight complex with the Fe3+ form of the haem iron of CYP3A4)
3. Mechanism-based inhibitors which require oxidation by a P459 enzyme: Oral contraceptive gestodene (CYP3A4) –> An oxidation product (postulated epoxide intermediate of gestodene) binds covalently to the enzyme which the destroys itself

Question 25

What is Glucuronidation?

Answer 25

Glucuronidation involves the formation of a high-energy phosphate (‘donor’) compound, uridine diphosphate glucuronic acid (UDPGA), from which glucuronic acid is transferred to an electron-rich atom (N, O or S) on the substrate, forming an amide, ester or thiol bond

Question 26

What are the routes of excretion?

Answer 26

Primary is urine
- Faeces –> purgative and liquid paraffins
- Exhaled air –> volatile anaesthetics and alcohol
- Saliva and Sweat –> rifampin
- Milk –> metronidazole and phenytoin

Question 27

What is enterohepatic circulation?

Answer 27

Various hydrophilic drug conjugates (particularly glucuronides) are concentrated in bile and delivered to the intestine, where the glucuronide can be hydrolysed, regenerating active drug

The free drug can then be reabsorbed and the cycle repeated

Question 28

How are drugs excreted from the kidney?

Answer 28

• Glomerular filtration: only remove those drugs or metabolites not bound to proteins.
• Tubular Secretion: 80% of the delivered drug passes on to the peritubular capillaries of the PT. Transferred to tubular lumen via OATs and OCTs
• Passive reabsorption