Elimination & Detox 2: Drug Metabolism

Question 1

CYTOCHROME P450…

= what/where is it & what does it do? (overall & 2)

the TYPE of reaction CYTOCHROME P450 does depends on…

Answer 1

= ENZYME IN CELL MEMBRANE OF ER of HEPATOCYTES that converts drugs into more POLAR & WATER-SOLUBLE compounds, so that they can be…
1. excreted by KIDNEY INTO URINE
2. liver can PERFORM CONJUGATION REACTIONS

the TYPE of reaction CYTOCHROME P450 does depends on the DRUG IT ACTS ON

Question 2

5 POSSIBLE REACTIONS via of CYTOCHROME P450?

Answer 2

1. HYDROXYLATION = (+) –OH
2. DEMETHYLATION = (-) –CH4
3. OXIDATION
4. DEAMINATION = (-) –NH3
5. DEHALOGENATION = removal of fluorine, chlorine, bromine, iodine

Question 3

what is the MOST COMMON phase I reaction?

Answer 3

OXIDATION

Question 4

what are the 2 MOST COMMON phase II reactions?

Answer 4

1. GLUCURONIDATION
2. ACETYLATION

Question 5

PHASE I vs. PHASE II reactions?

Answer 5

we can have NEITHER phases to have drug ELIMINATED BY KIDNEY, BOTH OR JUST ONE

Question 6

TRUE/FALSE

cytochrome p450 IS LIVER-SPECIFIC

Answer 6

FALSE, found in MANY ORGANS but MOSTLY IN LIVER BC THAT’S WHERE MOST OF METABOLSIM OCCURS

Question 7

what do drugs have to do to get enacted on by CYTOCHROME P450? (2 steps)

Answer 7

1. must GET INTO HEPATOCYTES
2. BIND TO IRON on the HEME

Question 8

CYTOCHROME P450 requires ___ & ___ ___ to ____

Answer 8

COFACTORS, NADPH REDUCTASE, WORK

Question 9

CONJUGATION REACTIONS are PHASE ___ REACTIONS

Answer 9

II

Question 10

ACETYLATION…

what phase is this?

what KIND of reaction is this?

facilitated by WHAT ENZYME? where is it mostly found?

what happens in it?

Answer 10

PHASE II

CONJUGATION REACTION

facilitated by ACETYL TRANSFERASE, mostly found in LIVER

adding ACETYL COA

Question 11

FIRST PASS EFFECT…

= definition

LOW extraction drugs? (3, definition, how it relates to first pass effect & bioavailability)

HIGH extraction drugs?
(3, definition, how it relates to first pass effect & bioavailability)

Answer 11

= when ORAL drugs come into GI LUMEN and METABOLIZED, enter PORTAL VEIN; how much the INITIAL LIVER METABOLISM affects them

LOW extraction drugs
1. NOT MUCH metabolism of that drug occurs IN LIVER, can EASILY GET TO THE REST OF THE BODY
2. DOES NOT HAVE SIGNIFICANT FIRST PASS EFFECT
3. HIGH BIOAVAILABILITY

HIGH extraction drugs
1. a LOT of metabolism of the drug OCCURS IN THE LIVER, DOES NOT EASILY GET TO THE REST OF THE BODY
2. HAS SIGNIFICANT FIRST PASS EFFECT
3. LOW BIOAVAILABILITY

Question 12

ENTEROHEPATIC RECYCLING…

requires the substance being recycled to…

4 steps?

Answer 12

requires the substance being recycled to BE EXCRETED IN THE BILE

steps?
1. substance EXCRETED IN BILE as GLUCURONIDATED METABOLITES

2. bile enters the DUODENUM
3. MICROBIOTA in SI REMOVES the GLUCURONIC ACID to RESTORE DRUG TO PARENT DRUG
4. PARENT DRUG can be ABSORBED AGAIN

Question 13

generation & excretion of BILE helps with the ____ of ____

3 numerical parameters for whether a drug is EXCRETED IN BILE or URINARY SYSTEM?

drugs excreted into the BILE must have a ___ ____ ___, making them often ___ substances

Answer 13

ABSORPTION, FATS

3 parameters?
1. <300 DALTONS = URINARY
2. 300-500 DALTONS = EITHER ONE
3. >500 DALTONS = BILE

DRUGS EXCRETED INTO THE BILE MUST HAVE A STRONG POLAR GROUP, MAKING THEM OFTEN AMPHIPATHIC SUBSTANCES

Question 14

how does GLUCURONIDATION affect how a drug is EXCRETED?

Answer 14

INCREASES likelihood of EXCRETION INTO BILE by INCREASING MOLECULAR WEIGHT & POLARITY

Question 15

if an animal has RENAL DZ, we should choose drugs that have WHAT 2 TRAITS & why?

Answer 15

choose drugs that are LARGER IN MOLECULAR WEIGHT & HAVE STRONG POLAR GROUPS so that they’re MORE LIKELY TO BE EXCRETED IN BILE since urinary system is likely compromised

Question 16

what species DO NOT have a gallbladder? (4)

this usually DOES NOT have…

Answer 16

1. HORSES
2. CERVIDS
3. RATS
4. SEVERAL BIRDS (pigeons & psittacines)

usually DOES NOT HAVE A CLINICAL EFFECT

Question 17

if a drug IS NOT METABOLIZED, what happens to it?

Answer 17

it is DIRECTLY EXCRETED

Question 18

PHARMACOGENOMICS…

= definition

Answer 18

= the STUDY OF GENES that INFLUENCE the ABSORPTION, DISTRIBUTION, METABOLISM & EXCRETION of drugs within an individual

Question 19

differences in PHASE I CYP450 in… (+ 1 overall effect!)

GREYHOUNDS?

CATS?

HORSES?

MINI/MICROPIGS?

Answer 19

GREYHOUNDS = have LOWER CYP2B11 ACTIVITY than other dogs
–> likely the reason they have PROLONGED RECOVERY FROM PROPOFOL (anesthesia)

CATS = DO NOT HAVE CYP2B6 in LIVER
–> might contribute to HEPATIC NECROSIS W/ DIAZEPAM

HORSES = have LOW CYP2D ACTIVITY
–> contributes to MONENSIN TOXICITY (from cattle feed)

MINI/MICROPIGS = have INCREASED CYP activity IN GENERAL
–> NEED HIGHER DOSES OF EVERYTHING

Question 20

differences in PHASE II CYP450 in… (+ 1 overall effect!)

CATS? (1 effect)

DOGS? (3 effects)

Answer 20

CATS = CANNOT GLUCURONIDATE because they LACK THE ENZYME

1. this is why they have LOW ASPIRIN CLEARANCE & ACETAMINOPHEN TOXICITY

DOGS = DO NOT HAVE N-ACETYLTRANSFERASE, so CANNOT ADD ACETYL CoA TO DRUGS

1. SULFONAMIDE ADMINISTRATION can cause HYPERSENSITIVITY
2. PROCAINAMIDE is NOT METABOLIZED TO ACTIVE METABOLITE but IS STILL EFFECTIVE
3. HYDRALAZINE (vasodilator) has MUCH LONGER HALFLIFE IN DOGS > HUMANS

Question 21

THIOPURINE METHYLTRANSFERASE has VARIABLE activity depending on ___ of ____

what PHASE is this involved in?

Answer 21

BREED, DOG

PHASE II REACTION

Question 22

what DRUG are GIANT SCHNAUZERS susceptible to HYPERSENSITIVITY to? why?

what PHASE is this involved in?

Answer 22

GIANT SCHNAUZERS are prone to TOXICITY with AZATHIOPRINE because CANNOT METABOLIZE drugs ACTIVE –> INACTIVE metabolites due to THIOPURINE METHYLTRANSFERASE DEFICIENCY

PHASE II REACTION

Question 23

PIGS DO NOT HAVE ____ ____, and this is a PHASE ___ reaction

unsure of the….

Answer 23

SULFATE CONJUGATION, II

unsure of the CLINICAL SIGNIFICANCE

Question 24

BIRDS & REPTILES HAVE DIFFERENT TYPES OF ____ ____ ____

Answer 24

AMINO ACID CONJUGATION

unsure of the CLINICAL SIGNIFICANCE

Question 25

in OLDER PEOPLE, what trends do we tend to see with…

PHASE I METABOLISM?

PHASE II METABOLISM?

FIRST PASS METABOLISM?

Answer 25

PHASE I = PROLONGED

PHASE II = NO CHANGE

FIRST PASS = REDUCED 1% PER YEAR OF AGE

Question 26

how do the TWO PREGNANCY HORMONES affect METABOLISM?

Answer 26

1. PROGESTERONE = can INCREASE or DECREASE certain CYP450 activity
2. ESTROGEN = can DECREASE BILE ACID SECRETION

Question 27

ST. JOHN’S WORT..

what does it do?

Answer 27

INHIBITS CYP3A4 and CP2D6, so CAN HAVE SIGNIFICANT EFFECT ON METABOLISM

Question 28

effect of PHENOBARBITAL & KETOCONAZOLE on CYP450?

Answer 28

PHENOBARIBITAL = INCREASES the activity of CYP450

KETOCONAZOLE = DECREASES the activity of CYP450

Question 29

THERAPEUTIC DRUG MONITORING…

= definition

in order for this to work the PLASMA CONCENTRATION must…

2 purposes?

Answer 29

= measurement of PLASMA/SERUM CONCENTRATION of a drug we’re administering at PEAK (maximum concentration) or TROUGH (right before next dose)

in order for this to work the PLASMA CONCENTRATION must CORRELATE TO THE OBSERVED CLINICAL EFFECT

purpose?
1. to ASSESS LIKELIHOOD OF EFFICACY/RISK OF TOXICITY of a drug
2. to DIFFERENTIATE between DISEASE PROGRESSION & DRUG FAILURE

Question 30

what 4 categories (& give one example of a drug) do we use THERAPEUTIC DRUG MONITORING?

Answer 30

1. EPILEPSY/SEIZURES
   –> ex = PHENOBARBITAL
2. IMMUNOMODULATION
   –> ex = CYCLOSPORINE
3. ANTIMICROBIALS
   –> ex = AMINOGLYCOSIDES bc they can cause RENAL TOXICITY if too HIGH
4. CARDIOVASCULAR drugs
   –> ex = QUINIDINE

Question 31

THERAPEUTIC DRUG MONITORING…

4 main steps/what they mean

Answer 31

1. START UP = need a BASELINE to know WHAT’S WORKING
2. FOLLOW-UP = +/- depending on PATIENT STATUS/OWNER FINANCES
3. CHECK-UP = are patients STILL HEALTHY?
4. WHAT’S UP? = when there’s a problem; is it the concentration, type of drug, or do we need another drug?

Question 32

how do we SUBMIT SAMPLES for THERAPEUTIC DRUG MONITORING?

Answer 32

on AUBURN UNIVERSITY PHARM LAB