Pharmacokinetics & Drug Biotransformation

Question 1

Pharmacokinetic Variables (ADME)

Answer 1

-Absorption; How it crosses barriers
-Distribution
-Metabolization
-Excretion

Question 2

Four Methods in Which Drugs Cross Barriers

Answer 2

Different forms of permeation:

1. Aqueous Diffusion; If water soluble, water diffuses down it’s concentration gradients typically through aquaporins. Cannot cross this way if the molecule is highly charged or bound to a large protein
2. Lipid Diffusion: Lipid soluble drugs such as steroids. The ability to move between aqueous & lipid phases is important for good drug
3. Special carriers: Drug binds to the carrier, the carrier will internalize the drug and spit them out into the cell. This is not the target cell. Active transport & Facilitated diffusion
4. Endocytosis: Cell surface surrounds the drug, engulfs it, spits it out on the other side
   -Exocytosis: Secretion of a substance from the cell. Ex: Neurotransmitters are stored in membrane bound vesicles until ready to use

Question 3

Volume of Distribution (Vd)

Answer 3

-The space available in the body to contain the drug (theoretical number)
-Relates the amount of drug in the body to the amount of drug in the blood stream

Question 4

Clearance (Cl)

Answer 4

-Ability of the body to eliminate the drug. Predicts the rate of elimination in relation to drug concentration. Multiple organs play a role here

Question 5

Concentration (C), Target Concentration (TC), Rate of Elimination (ROE)

Answer 5

-C: The amount of drug given in a volume
-TC: The desired concentration at the effector site
-ROE: Predicted by clearance

Question 6

Vd & Cl in relation to drugs in the system

Answer 6

-The higher the Vd, the lower the amount of drug in the bloodstream
-The lower the Vd, the higher the amount of drug in the bloodstream

Vd along with clearance will determine the T1/2 of drugs

Question 7

First Order, Zero Order, Capacity Limited Elimination

Answer 7

1) First order elimination; how most drugs are eliminated from the body. Clearance remains constant, ROE varies

2) Zero order elimination; ROE remains constant. Clearance varies with concentration. Occurs when the body’s ability to eliminate a drug has reached its maximum capacity. (EtOH, ASA, phenytoin)

Capacity limited elimination happens when we have zero order elimination. This can start as first order, but because of the drug amount in the body can become zero-order/ capacity limited

Question 8

Flow Depend Elimination & The Extraction Ratio

Answer 8

Strictly depends on blood flow through the organ, and whether or not the drug is a high extraction drug.
High extraction means that a large portion of the drug is removed by the organ prior to reaching circulation.

The extraction ratio tells us how much of the drug was removed prior to reaching circulation. Depends on organ health

Question 9

Extraction Ratios

Answer 9

High : >0.7
Intermediate: 0.3-0.7
Low: <0.3

Question 10

Half Life ( T1/2)

Answer 10

-The time required for the body to eliminate half of the drug. Half life is dependent upon the extraction ratio, organ health, Vd, and clearance
-In “steady state” dosing (meaning no boluses of the drug have been given), it is generally assumed that it will take 4x half-lives in order to achieve target concentration. Conversely, it should take approximately 4x half lives for the drug to be eliminated from the body

Question 11

Accumulation

Answer 11

The drug continues to accumulate in the body until dosing stops. Can reach toxic levels of the drug if our dosing intervals are shorter than 4x half-lives

Question 12

Bioavailability (F)

Answer 12

The fraction of unchanged drug reaching systemic circulation

Question 13

Seven Routes of Administration & their (F)

Answer 13

1. IV 100%
2. IM 75 -100%
3. Sub-Q 75 -100%
4. PO 5 -<100%
5. Rectal 30 -<100%
6. Inhalation. 5 -<100%
7. Transdermal 80- 100%

Question 14

Peak & Trough

Answer 14

Peak: When a drug is at its highest concentration. Draw levels 5-10mins after administration
Trough: When the drug is at its lowest concentration. Draw levels 30 mins before next dose

Question 15

Drug Biotransformation

Answer 15

The drug is metabolically converted, either into an inactive metabolite or a metabolite that is more active.
Primarily occurs in the liver

Question 16

Active Drug & Prodrug

Answer 16

Active Drug: Sufficiently lipid soluble and stable to be given as is. Readily available to reach its intended site of action through a convenient route

Prodrug: An inactive precursor that is absorbed and converted into an active metabolite by a biological process (biotransformation)

Question 17

First Pass Effect

Answer 17

When an oral drug is absorbed, intact, from the small intestine and transported through the hepatic portal system through the liver, where it undergoes extensive metabolism before reaching systemic circulation

Question 18

Blood Flow Through The Liver (GI Tract)

Answer 18

GI tract —> absorbed into intestinal capillaries —> reaches the hepatic portal vein —> combines with the splenic vein a series of capillaries (portal system, the hepatic sinusoids)
These capillaries are very leaky. The drug can leak from the capillaries into the hepatocytes where biotransformation will occur. Drug is either put back into the bloodstream or excreted through the bile.

Once back in the bloodstream —> enters the hepatic vein —> to the vena cava —> heart & systemic circulation

Question 19

Blood Flow Through The Liver (IV Drugs)

Answer 19

Vena Cava–> Heart –> Aorta –> Hepatic Artery–> Hepatic Sinusoids

Question 20

Phase I Metabolic Reaction
(Oxidation, Reduction, Dehydrogenation, Hydrolysis)

Answer 20

Phase I Reactions:
-Converts a drug into a more polar metabolite.
-Adds or unmasks a functional group (-OH, -NH)
-Usually makes the drug more readily excretable; a lipophilic drug becomes more hydrophilic

Oxidation: Loss of an e-
Reduction: Gain of an e-
Dehydrogenation: Remove an OH group
Hydrolysis: Breaks down water

Oxidation and reduction always happen together

Question 21

Cytochrome P450
Generic Cyp450 Pathway

Answer 21

Cytochrome P450: A protein with a heme. Function is to introduce an oxygen to xenobiotic compound

Cyp450 Oxidation-Reduction requires P450, P450 Reductase (flavoprotein), NADPH, and molecular oxygen

P450 (Fe3+) combines with RH group (drug)
P450(Fe3+)-RH
–> NADPH donates e- to P450 reductase –> P450 (Fe2+)-RH
–> NADPH donates another e- to P450 reductase, reduces molecular oxygen–> O2-P450(Fe2+)-RH
–> Activated oxygen is transferred to the drug substrate group to form P450(Fe3+)-ROH = making the drug more water soluble

Question 22

Cytochrome P450 Isoforms (Including wildtype)

Answer 22

CYP3A4- Responsible for metabolization of 50% of all drugs undergoing Phase I
CYP2B6, CYP2D6 also important

CYP3A4 *1 is the “wild type,” meaning, most commonly seen

Question 23

Phase II Reactions: Conjugation

Answer 23

-Adding molecules to something typically resulting in the compound being more polar, readily excretable, and inactivated

Types of Conjugation:

-Glucuronidation: UDP glucuronic acid carries a glucose-like substance to the drug compound & attaches it.

-Glutathione: Glutathione-S-Transferase attaches glutathione molecule. Important for detoxification

-Acetylation
-Sulfation
-Glycine
-Methylation
-Water conjugation

Question 24

Hepatic Enzyme Induction

Answer 24

Induction of P450: Increases the presence of P450
DECREASED drug effect if P450 deactivates drug
INCREASED drug effect if P450 activates drug

Ex: Drug 1 given (metabolized by P450)
Drug 2 given (inducer of P450) –> Drug 1 becomes inactivated much more quickly

Prodrug given –> activated by P450–> Drug 3
Drug 2 also given –> can reach toxic levels of drug 3 quickly because Drug 2 is an inducer of P450

Question 25

Hepatic Enzyme Inhibition

Answer 25

P450 Inhibition: Decrease activity or irreversibly inhibit

Ex:
Drug 1 given (inactivated by p450)
Drug 4 is given (inhibits P450) –> Drug 1 can reach toxic levels

Question 26

Tylenol Metabolism

Answer 26

95% of APAP will undergo two Phase II reactions. The other 5% undergoes the P450 pathway

1. Glucuronidation –> APAP glucuronide–> some APAP+ glucuronide will cross the BBB–> remaining will be transported back into the intestine by ABC transporters–> usually excreted in feces
2. Sulfation –> APAP sulfate–> excreted
   Accounts for 95% of Tylenol’s metabolism

If traditional pathways are overwhelmed, an alternative pathway has to be activated:

GSH (Glutathione) Conjugation; Little or no hepatotoxicity will occur as long as there is hepatic GSH available for conjugation. If hepatic GSH is being depleted faster than it can be regenerated, reactive, toxic metabolites begin to accumulate. A reactive metabolite (N-acetylbenzoiminoquinone) reacts with cell membranes, proteins, and sugars resulting in hepatotoxicity and death

Question 27

Additional Factors That Affect Drug Metabolism

Answer 27

-Diet; Charcoal Broiling (Induces CYP1A)
Grapefruit juice (Inhibits Cyp3A)
-Cigarette Smoke
-Age, Sex
-Disease status
-Genetics

Question 28

6MP & TPMT Mutations

Answer 28

TPMT Mutations mean that they may not be able to metabolize this drug properly. The enzyme is less active. Will need reduced dose or may not be able to take the drug at all

Question 29

Warfarin & CYP2C9

Answer 29

CYP2C9 isoform means that the patient is either a slow metabolizer or an ultra rapid metabolizer

Question 30

Herceptin & HER2

Answer 30

If the tumor is overexpressing HER2, the patient is a candidate for Herceptin therapy

Question 31

Why is pharmacogenomics important in personalized medicine?

Answer 31

We are studying genetic factors and how they affect variation in drug response.
Genetic information is used to guide drug and dosing selection

Question 32

Role of drug transporters & drug efflux transporters

And factors that affect drug transport

Answer 32

-Drug transporters are located in the endothelial cells of many tissues (intestinal, renal, hepatic) and mediate selective uptake of endogenous compounds and xenobiotics
-Molecular weight, pKa, lipid solubility, and plasma protein
-Drug efflux transporters are membrane proteins that specialize in expelling foreign molecules

Question 33

Important ABC transporters & their drug affinity

Answer 33

-These transporters bind ATP. ATP binding cassette (ABC)

-ABCB: Broadest substrate specificity; Antineoplastics, HIV protease inhibitors, abx, antidepressants, antiepileptics, opioids
-Drug interactions w/ ABCB: Cyclosporine, quinidine, ritonavir & dig.
When loperamide & quinidine are given together, causes CNS effects
-ABCC: Antineoplastics
-ABCG: Breast cancer resistance protein; antineoplastic, toxins, food-borne carcinogens, folate transport

Question 34

Drug transporters in different organs & their overall effects

GI, Liver, BBB

Answer 34

GI tract: Transporters are localized in microvilli, transport drugs from the intestine into the bloodstream
Liver: Transporters typically bring drug into the liver.Metabolize xenobiotics and excrete metabolites into bile
BBB: Allows certain drugs to cross into the BBB (highly hydrophobic), but overall most things are going to be pushed back out

Question 35

Components of the intact BBB

Answer 35

-Functional separation of the circulating blood from the extracellular fluid in the CNS
1. Specific transporters
2. Endothelial cells & tight junctions
3. The cells that surround it; astrocytes and pericytes (podocytes)