Pharmacokinetics

Question 1

What are the major mechanisms for transport across biological membranes?

Answer 1

• Passive diffusion (increase membrane SA, increase permeability constant (P); increase thickness, decrease P). Limited to nonionized lipid soluble drugs
• Filtration
• Endocytosis
• Facilitated diffusion
• Activated transport

Question 2

Describe ion trapping.

Answer 2

Ions can’t diffuse across a membrane. When a weak acid or weak base dissociates, it’s charged ions get stuck on one side of the membrane.

Has therapeutic implications for the renal excretion of drugs - increasing urinary pH enhances the renal excretion of a weak acid while lowering the urinary pH enhances the excretion of a weak base.

Question 3

What are the 2 major carrier-mediated drug transport mechanisms?

Answer 3

• ABC (ATP-binding cassette) superfamily: Primarily active transporters usually moving substances out of cells. ex. p-glycoprotein
• SLC (solute carrier) superfamily: facilitated and active transporters that work through a secondary mechanism. Can move substances in or out of cells. Ex. serotonin reuptake transporter.

Question 4

What are some advantages and disadvantages of the common routes of drug administration?

Answer 4

-Orally: Cheap, easy administration, safety, patient compliance. Destroyed in GI, 1st pass metabolism, variable rate.

Administer in IV, you will know exactly dose and timing, but there is no second chances, whereas orally you have a window of time. 100% bioavailability if administered this way.

• Sublingualy,: bypass 1st pass.
• Rectal: bypass 1st pass mostly

Question 5

Define bioavailability.

Answer 5

Is a measure of the fraction of an administered dose of a drug that is absorbed into the systemic circulation.

Formulation can alter bioavailability; includes such factors as disintegration rate, dissolution rate, solubility of preparation, particle size, and coatings

Question 6

What are the main factors that affect the internal distribution of a drug?

Answer 6

• Relative tissue perfusion rates
• Plasma protein binding
• Partitioning between plasma and tissues

Question 7

What is the apparent volume of distribution?

Answer 7

Reflects relative affinity of a drug for the whole body and for plasma. Anything that pulls drug from plasma into tissues increases VD; anything that keeps drug in plasma decreases VD.

Question 8

What are the mechanisms for terminating a drug?

Answer 8

• Storage (redistribution)
• Excretion
• Biotransformation

Question 9

Describe the process of drug redistribution.

Answer 9

Two Phases:

• flow dependent..drug distributes rapidly to tissues with large flows
• Distribution of drug to tissues with low flows.

Example:
Thiopental - high lipid:water partition coefficient, rapid onset but short duration of action

1. After a single dose, rapid equilibration between plasma and brain accounts for rapid onset
2. Redistribution of drug from brain to fat accounts for short duration of action

Question 10

What is renal clearance and what are the major mechanisms by which drugs are excreted by the kidney?

Answer 10

Defined as volume of plasma entirely cleared of drug or metabolite /unit of time by the kidney.

Mechanisms:

• Glomerular filtration (only free, unbound drug or metabolite in plasma is filtered)
• Reabsorption (Both facilitated transport and passive diffusion; acidify urine increase excretion of weak base..alkalize urine increase excretion of weak acid)
• Secretion (active transport for acids and bases)

Question 11

What are the two major phases of drug biotransformation?

Answer 11

• Phase 1: drug has functional group chemically added or exposed, most common rxn is oxidation.
• Phase 2: synthetic conjugation reaction adds a large molecule to drug or Phase 1 metabolite. Glucoronidation most common.

Biotransformation usually results in metabolite more polar than parent compound and thus more easily eliminated

Question 12

What are the major organs of biotransformation?

Answer 12

*Liver
Also could be:
-GI tract
-Kidney
-Lungs
-Skin
-Plasma

Question 13

What are the major components of the microsomal drug oxidizing system?

Answer 13

Cytochrome p450 (CYP) enzymes contained in the smooth endoplasmic reticulum. More than 50 ID’d.
Rate of drug biotransformation among individuals is variable and dependent upon:
-concentration of CYP
-forms of CYP expressed

Question 14

What other factors can affect enzymatic pathways responsible for drug transformation?

Answer 14

• Drugs
• Genetic differences
• Age
• Diet
• Environmental (smoking and factory work induces CYPs)
• Pregnancy