Lecture 75

Question 1

If a drug has a significant (75% or more is metabolized) ____ first pass effect, it may need to be administered via a non-oral route. Suppositories are alternatives because the blood from the colon doesn’t go directly to the liver.

Answer 1

HEPATIC first pass effect

Question 2

______ is the term that describes the percent or fraction of drug that reaches systemic circulation for distribution around the body.

Answer 2

BIOAVAILABILITY.

Question 3

Some drugs experience ______ cycling, whereby the liver pumps some of the drug into the common bile duct. From there, it enters back into the intestine, then back to the liver. Similar to drugs binding albumin in the blood, this cycling is an example of sequestration of the drug (decreases its bioavailability).

Answer 3

ENTEROHEPATIC cycling.

Question 4

Kidneys can only excrete ____soluble forms of drugs. ____soluble molecules can undergo tubular reabsorption whereby they diffuse out of the kidney and back into the blood.

Answer 4

WATERWATER

Liposoluble

Question 5

____-trapping is the term that describes taking advantage of the charge of a drug to increase or decrease its excretion through the urine by adjusting the pH of the Urine (Think about how you would want to alter the pH if the drug was a weak acid vs a weak base). Keep in mind, the drug must have a _____ close to the pH of urine in order to do this.

Answer 5

ION-trapping. Keep in mind the drug must have a pKa close to the pH of urine.

Question 6

_____ is a drug that is excreted in large amounts via tubular secretion because it remains charged after being pumped from the blood into the nephron in the PCT. If coupled with another weak acid drug (i.e. probenecid,) less _____ is pumped into the nephron (because probenecid competes for the same pumps) and thus less is excreted.

Answer 6

PENICILLIN

Question 7

Most biotransformation of drugs occurs in the ____.

Answer 7

LIVER

Question 8

The vast majority of the time, the metabolite of a drug is more ____soluble than the drug was originally.

Answer 8

Metabolites are more WATER-soluble.

Question 9

Synthetic reactions are also called Conjugations. These reactions typically occur with ____soluble drugs, whereby a ______soluble molecule is added to the drug. _____ transferases (adds Glucuronic acid to drug) and _____transferases (adds sulfate to drug) are examples of liver enzymes that perform these conjugation reactions. These enzymes specifically target ____ groups on the drug for their respective mods.

Answer 9

These reactions typically occur with LIPOsoluble drugs, whereby a WATER-soluble molecule is added to the drug. GLUCURONYL transferases and SULFOtransferases are examples of liver enzymes that perform these conjugation reactions. They specifically target OH groups for their respective mods.

Question 10

Glutathione is a molecule in the liver that also participates in conjugation reactions. It is a ____peptide that combines with highly reactive metabolites to detoxify them. It always combines with these metabolites via its ____ group.

Answer 10

It is a TRIpeptide and it always combines via its SH group.

Question 11

There are 3 NON-synthetic reactions:
1. \_\_\_\_\_
2. \_\_\_\_\_
3. \_\_\_\_\_
and CYP450s are the most abundant enzymes that catalyze \_\_\_\_\_ reactions.

Answer 11

1. Oxidation
2. Reduction
3. Hydrolysis
   and CYP450s are the most abundant enzymes that catalyze OXIDATION

Question 12

An example of a reduction reaction would be the conversion of Testosterone to ______ via the enzyme 5-aplha-reductase.

Answer 12

Testosterone to Dihydrotestosterone

Question 13

Two families of enzymes, esterases and amidases, participate in drug _____ reactions. An example would be the conversion of Aspirin to ____ and ____ via and esterase.

Answer 13

Esterases and amidases participate in drug HYDROLYSIS reactions. An example would be the conversion of Aspirin to SALICYLIC ACID and ACETIC ACID

Question 14

If acetominophen doses are too high, it can deplete liver stores of sulfate, glucuronic acid, and glutathione for conjugation, at which point it will be _____ to form a reactive metabolite (NAPQI.) This metabolite will bind to any macromolecule it comes in contact with and can lead to cell death.

Answer 14

If the dose is too high, it can be OXIDIZED to form a reactive metabolite (NAPQI)

Question 15

_____ nucleotide polymorphisms are the most important gene mutations with respect to drug metabolizing enzymes.

Answer 15

SINGLE

Question 16

P4502C9 (CYP2C9) is the CYP450 that metabolizes Warfarin. The wildtype has Arg at the 144 position, but when changed to ____, it reduces the activity of this enzyme by ___%.

Answer 16

But when it’s changed to CYS, it reduces the activity of this enzyme by 50%

Question 17

If 2 drugs are metabolized by the same enzyme, they will compete for it. This is termed _____ of biotransformation.

Answer 17

INHIBITION

Question 18

In the case that drug A increases the transcription of enzymes that metabolize another drug (Drug B), the therapeutic effect of drug B is decreased. This is termed _____ of biotransformation.

Answer 18

INDUCTION

Question 19

Phenobarbitol is an inducer of biotransformation for _____, which, like Warfarin, is given to prevent blood clotting.

Answer 19

DICUMAROL

Question 20

_____ is an inducer of CYP2E1, one of the CYP450s that forms the reactive metabolite NAPQI from Acetominophen.

Answer 20

ETHANOL