2013-08-26 Drug Metabolism

Question 1

Describe Phase I Metabolism

Answer 1

Phase I metab rxns add small functional groups to the drug/toxin/exogenous substance to make it more water soluble

Question 2

Describe Phase II Metabolism

Answer 2

Phase II metab rxns conjugate the products of Phase I rxns make them more easily eliminated

Question 3

Describe key enzymatic rxns needed for drug metabolism

Answer 3

Phase II rxns:
–glucuronidation via UDP-GT in liver (uridine diphosphate glucuronyltransferase); MOST COMMON [see other card]

–sulfate conjugation via sulfotransferases ; SECOND MOST COMMON

–glutathione conjugation via GSTs (glutathione-S-transferases)

–methyl conjugation via methyltransferases and SAM (S-adenosylmethionine) as methyl donor

–amino acid conjugation with glycine, glutamine

–N-acetylation conjugation via N-acetyltransferases [see other card]

Question 4

Discuss the clinically important factors that can affect drug metab

Answer 4

P450 induction via acute or chronic use of another drug, diet, OTCs, supplements, smoking, toxin exposure etc.
[MORE]

Question 5

List commonly used substances that can have a serious impact of drug activity/metabolism.

Emphasize need to inform pts of drug interactions

Answer 5

cigarettes

grapefruit juice - INCR bioavailability b/c of furanocumarins inhibit CYP3A4 metab of drugs + inhibition of Pgp-mediated drug efflux in liver and intestines

St. John’s Wort

cruciferous (from Brassicaceae family =) vegetables (e.g. brussel sprouts, cauliflower, cabbage etc.) INCR metab probs via P450 induction

grilled meat INCR metab b/c of benzo[a]pyrene induced P450

Question 6

Cytochrome P450

Answer 6

large multi-gene superfamily (20 Cyp families total) of enzmyes mostly involved in Phase I metab

• -absorbs light at 450nm thus the name
• -Cyp families I-IV metab exogenous substances
• -Almost all drugs are metab’d by the CYP fam
• -Most are expressed in the LIVER

age and sex-dependent diffs in distribution, of specific P450s that ∆ pattern of metab among diff individuals

Question 7

What are the isoforms responsible for >95% of all drugs?

Which of thus is most abundantly produced?

Answer 7

CYP...
...1A2
...2C9/2C19 (10-12%)
...2D6 (25%)
...3A4 (most abundant; resp for metab of >60% all drugs)

NOTE: drugs may undergo many metab steps by many diff P450s simultaneously

Question 8

What happens to metabolites of P450 reactions?

Answer 8

May be excreted directly or undergo additional Phase II steps

Question 9

Define: biotransformation

Answer 9

a.k.a. metabolism

Question 10

Compare chemistry and pharmacology of drug to its metabolite.

Answer 10

Metabolites are usually more polar and less active than parent compound.

However, some metabolites are more active as in the case of pro-drugs (e.g. codeine —> morphine) and pro-toxins (benzo[a]pyrene —> benzo[a]pyrene diol epoxide —> scrotal cancer in chimney sweeps)

Question 11

Molecular mech of P450 induction

Answer 11

nuclear receptors are stimulated by various ligands (drugs, foods, etc.) that alter the expression of different CYP genes

Question 12

The primary purpose of Phase I metabolism to the parent compound include all of the following except?
A. to make the parent compound more lipophilic
B. to make the parent compound more hydrophilic
C. to provide a substrate for Phase II metab
D. to enhance excretion

Answer 12

A. Phase I metab makes parent compound LESS lipophilic

Question 13

∆s in [UDP-GT] throughout the life span and clinical significance

Answer 13

• *UDP-GT low at birth and also declines in old age
• -neonatal hyperbilirubinemia —> CNS damage
• -Gray baby syndrome: babies can’t metab chloramphenicol and so get excessive levels w/ assoc’d toxicitires
• -Crigler-Naijar syndrome: near total genetic def in hepatic UDP-GT; jaundiced babies w/ death in early childhood =(

Question 14

β-glucuronidase

Answer 14

“In the gut, brush border β-glucuronidase converts conjugated bilirubin to the unconjugated form for reabsorption. Beta-glucuronidase is also present in breast milk, which contributes to neonatal jaundice.” [wiki]

• -enetero-hepatic circulation of drug prolonging retention time
• -qqch about gut microbiome?

Question 15

List factors that influence drug metabolism

Answer 15

genetics
sex
dz states
other drugs, food, enviro factors
age
developmental stage
plasma protein levels
tissue-specific accumulation
physiological barriers
active transport across membranes

Question 16

N-acetylation conjugation and clinical significance

Answer 16

N-acetyltransferase present in cytosolic liver, kidney, lung and intestine

• -bimodal distribution of “fast” and “slow” acetylators; also some “intermediates” we know the genes NAT1 and NAT2
• *slow acetylators are homozygous for autosomal gene and susceptible to dose-dependent drug toxicities

Japanese, Chinese and Alaska Natives: slow acetylators
Egyptians, Israeli and Scandanavians

–important for metab of isoniazid, sulfamethazine (abx), p-aminosalicylic acid (TB), hydralazine

Question 17

Clicker Q: Phase II metab results in what primary chemical change to parent compound?

Answer 17

conjugation

Question 18

Dz states that impair hepatic metabolism

Answer 18

malaria
schistosomiasis
cancer (even if not in the liver itself)
hepatitis
jaundice
cirrhosis

Question 19

effects of ethanol ingestion: acute vs. chronic

Answer 19

effects of acute vs. chronic often opposite

acute: inhibits metab, prolongs effects esp of CNS depressants via competitive inhibition

chronic: INCREASES drug metab and clearance via induction of P450 and other enzymes
- -dramatically decreases T1/2 of many drugs

Question 20

Factors affecting drug absorption

Answer 20

lower CO (30% decr)
decreased blood flow (40-50% decr)
altered gut motility

Question 21

factors affecting drug distribution

Answer 21

hypoalbuminemia (20% decrease)
qualatative ∆s in drug binding sites
decreased relative muscle mass
increase % body fat and total body water

Question 22

factors affecting drug metab in the elderly

Answer 22

1. metab: reduced hepatic mass, blood flow and enzyme activity
2. excretion: reduced RBF from reduced CO, GFR, tubular secretory activity and number of nephrons (kidney function decr 10%/decade after your 20s)
3. receptors: decr in number, affinity and qualitative responsiveness

Question 23

Drug Transporters

Answer 23

ATP-Binding Cassette (ABC) transporter proteins include:

• -Pgp (p-glycoprotein) transports mostly amphiphilic parent molecules
• -MRP mostly transports Phase II conjugates