Drug Metabolism

Question 1

Xenobiotics

Answer 1

foreign substances that are not naturally found in the body

Question 2

first-pass effect

Answer 2

Substances absorbed via the GI tract go to the liver before they enter general circulation, then may either be redelivered to the liver or go to some other tissue

Question 3

Often the same chemical property that enhances bioavailability of drugs may also make ____ difficult

Answer 3

Often the same chemical property that enhances bioavailability of drugs may also make renal excretion difficult

Question 4

phase I reactions

Answer 4

Redox

Question 5

phase II reactions

Answer 5

Conjugation/hydrolysis

Question 6

Oxidation reactions typically transform the drug into more ____ metabolites by _____

Answer 6

Oxidation reactions typically transform the drug into more hydrophilic metabolites by adding or exposing polar functional groups such as hydroxyl (-OH) or amine (-NH2) groups

Question 7

Most liver enzymes which catalyze phase I reactions are _____.

Answer 7

Most liver enzymes which catalyze phase I reactions are heme protein mono-oxygenases of the cytochrome P450 class.

Question 8

Importance of iron to the p450 enzymes

Answer 8

The iron within the heme group of the p450 enzyme is what activates oxygen for the p450 oxidation reactions.

This is so synonymous with p450 function that the p450 enzmyes are sometimes also called “oxygen guns”

Question 9

alcohol dehydrogenase

Answer 9

non-p450 oxidative liver enzyme

oxidizes alcohols to their aldehyde derivatives as part of the overall process of excretion. These enzymes are the basis for the toxicity of methanol. Methanol is oxidized by alcohol dehydrogenase to formaldehyde​

Question 10

monoamine oxidase

Answer 10

non-p450 oxidative liver enzyme (also found outside of the liver)

responsible for the oxidation of amine-containing endogenous compounds such as catecholamines and tyramine.

Question 11

Hydrolysis of ester- and amide-containing drugs is sometimes included among the. . .

Answer 11

. . . phase I reactions, despite its mechanism (hydrolysis) more closely resembling that of a phase II reaction.

Question 12

____ is the most common group that is conjugated to drugs to facilitate their excretion

Answer 12

Gluconuric acid is the most common group that is conjugated to drugs to facilitate their excretion

Question 13

Common phase II adducts

Answer 13

Glucuronic acid, acetate, glycine, sulfate, glutathione, and methyl groups

Question 14

____, an important exception to the phase II reactions, does not increase drug hydrophilicity

Answer 14

Methylation, an important exception to the phase II reactions, does not increase drug hydrophilicity

Question 15

Enzymes involved in redox and conjugation/hydrolysis reactions often ____.

Answer 15

Enzymes involved in redox and conjugation/hydrolysis reactions often compete for substrates

Question 16

Following phase I and II reactions, drug metabolites may be too polar to ______.

Answer 16

Following phase I and II reactions, drug metabolites may be too polar to leave the cell

For this reason, liver cells have pumps which may actively secrete processed, highly hydrophilic molecules

Question 17

P-glycoprotein

Answer 17

An example of a hepatocyte ATP-dependent hydrophilic small molecule pump

Also expressed in various other tissues to serve similar functions

Question 18

P-Glycoprotein in the placenta

Answer 18

Actively pumps drugs back into the mother’s blood

Question 19

Pathologic overexpression of ______ can play a role in development of resistance of cancer cells to drugs.

Answer 19

Pathologic overexpression of P-glycoprotein can play a role in development of resistance of cancer cells to drugs.

Question 20

The metabolism of drugs from the portal circulation (i.e., the first-pass effect) often requires the transport of compounds into hepatocytes via ____ and ____.

Answer 20

The metabolism of drugs from the portal circulation (i.e., the first-pass effect) often requires the transport of compounds into hepatocytes via the organic anion transporting polypeptide (OATP) and the organic cation transporter (OCT) family of proteins.

Question 21

____ are particularly relevant for the metabolism of several statins.

Answer 21

OTAP and OCT are particularly relevant for the metabolism of several statins.

Question 22

organic anion transporter (OAT) family

Answer 22

responsible for renal excretion of many clinically important anionic drugs, such as β-lactam antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and antiviral nucleoside analogs.

Question 23

Induction

Answer 23

Occurs when one drug drug induces upregulation of a P450 enzyme that metabolizes the another drug, resulting in faster activation/inactivation of the second drug.

The primary mechanism is through increased transcription

Question 24

Carbamazepine’s interaction with p450 enzymes

Answer 24

An antiepileptic drug, not only induces P450 3A4 but also is metabolized by P450 3A4. Hence, carbamazepine increases its own metabolism by inducing P450 3A4.

Question 25

Inhibition

Answer 25

When addition of a second drug intereferes with the metabolism of the first drug. May be the result of competitive antagonism or irreversible inhibition.

Question 26

Mitomycin C

Answer 26

A naturally occurring compound that is activated to a powerful DNA alkylating agent after it is reduced by several enzymes including a cytochrome P450 reductase. Mitomycin C selectively kills hypoxic cancer cells in the core of solid tumors because: (1) these cells have increased levels of the cytochrome P450 reductase that activates mitomycin C; and (2) reoxidation of the drug is inhibited under hypoxic conditions.

Question 27

Neonatal jaundice

Answer 27

results from a **deficiency of the bilirubin-conjugating enzyme UDPGT**

Question 28

Gray baby syndrome

Answer 28

Excretion of **chloramphenicol** requires an oxidative transformation followed by a conjugation. The oxidation metabolite of chloramphenicol is toxic; if this metabolite **fails to undergo conjugation**, it can build up in the plasma and may reach toxic concentrations. Toxic levels of the metabolite can cause neonates to experience **shock and circulatory collapse**, leading to the **pallor and cyanosis** that give the syndrome its name.

Question 29

In the elderly, a general ____ in metabolic capacity is observed

Answer 29

In the elderly, a general **decrease** in metabolic capacity is observed

Question 30

Grapefruit juice effect and hepatic metabolism

Answer 30

The **psoralen derivatives and flavonoids** in grapefruit juice **inhibit both P450 3A4 and MDR1** in the small intestine. Inhibition of P450 3A4 significantly **decreases the first-pass metabolism of co-administered drugs** that are also metabolized by this enzyme, and inhibition of MDR1 significantly increases the absorption of co-administered drugs that are substrates for export (**efflux**) by this enzyme.

Question 31

Rifampin

Answer 31

Antibiotic which induces p450 enzmyes that **cause estrogen-based hormonal contraception to be ineffective** at standard doses due to metabolism of the common estrogenic component 17α-ethynylestradiol

Question 32

Tolerance

Answer 32

when a drug induces its own metabolism and thus reduces its efficacy over time

Question 33

Because drugs are often prescribed in combination with other pharmaceuticals, careful attention should be paid to drugs that are \_\_\_\_

Answer 33

Because drugs are often prescribed in combination with other pharmaceuticals, careful attention should be paid to drugs that are **metabolized by the same hepatic enzymes**

Question 34

One treatment for methanol poisoning is the administration of \_\_\_\_, which competes with methanol for oxidation by alcohol dehydrogenase

Answer 34

One treatment for methanol poisoning is the administration of **ethanol**, which competes with methanol for oxidation by alcohol dehydrogenase

Question 35

In addition to hepatic and renal regulation, ___ is a major regulator of drug metabolism

Answer 35

In addition to hepatic and renal regulation, **the thyroid** is a major regulator of drug metabolism

Question 36

At steady state, ____ equals \_\_\_\_.

Answer 36

At steady state, **drug infusion** equals **drug elimination**.

Question 37

Relationship between drug infusion and elimination kinetics

Answer 37

Question 38

A drug will reach steady state in about ____ half-lives

Answer 38

A drug will reach steady state in about **four** half-lives

Question 39

The sole determinant of the rate that a drug approaches steady state is . . .

Answer 39

The sole determinant of the rate that a drug approaches steady state is **the t_1/2** The rate of approach to steady state is **not affected by the rate of drug infusion**. Rather, **increasing the infusion rate will** **increase the steady state concentration**.

Question 40

Oral dosing and IV infusion pharmacokinetics

Answer 40

Question 41

Loading dose calculation

Answer 41

Question 42

A loading dose is most useful for drugs that are eliminated from the body \_\_\_

Answer 42

A loading dose is most useful for drugs that are eliminated from the body **relatively slowly**

Question 43

Dosing

Answer 43

Question 44

Role of P glycoprotein in various tissues

Answer 44

Question 46

Most important of the p450 enzymes

Answer 46

CYP2D6 and CYP3A4 Both also highly polymorphic

Question 47

Variants of ___ may classify individuals as "ultrametabolizers" or "undermetabolizers"

Answer 47

Variants of **CYP2D6** may classify individuals as "ultrametabolizers" or "undermetabolizers"

Question 48

Some ____ inhibit the activity of CYP2D6

Answer 48

SSRIs

Question 49

Codeine is a \_\_\_\_.

Answer 49

Codeine is a **prodrug**. It is metabolized to morphine in the liver by CYP2D6. On this basis, it is though to be **substantially more dangerous to use than just plain old morphine**. This is because: 1. Ultrametabolizers may metabolize codeine too quickly, resulting in morphine toxicity 2. Undermetabolizers may not obtain pain relief because they metabolize codeine too slowly There is seriously **no reason to give codeine instead of morphine**

Question 50

Only step of ADME that P glycoprotein has no effect on

Answer 50

Metabolism

Question 51

the 4 x t_1/2 rule only applies to \_\_\_.

Answer 51

the 4 x t_1/2 rule only applies to **1st order elimination kinetics**.

Question 52

R_D calculation

Answer 52

R_D = [Drug]_{steady state} x R_C x F^-1 Where R_C = 0.693 x V_d / t_1/2

Question 53

V_d is often given as

Answer 53

L/kg

Question 54

Definition of R_D'

Answer 54

R_D' may be defined as **R_D' = R_D x F** such that **R_D' / R_C = [Drug]_{steady state}**