Lecture 4: Pharmacokinetics Part 2 Flashcards Preview

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1

The greatest contributor overall to variances in pharmacokinetics between individuals is

Drug elimination

2

Drugs are eliminated from the body via two processes:

Metabolism and excretion.

3

The major determinants of drug action in the body is

Elimination processes (metabolism and excretion)

4

Major routes for direct drug excretion

Urine, bile

5

Minor routes for direct drug excretion

Saliva, sweat, breast milk, other bodily fluids, exhalation

6

Most drugs require ______ before they can be efficiently excreted from the body

Metabolism/biotransformation

7

(T/F): Most drugs are lipophobic and only partially ionized at physiological pH

False. Most drugs are lipoPHILIC and only partially ionized at physiological pH

8

Why are most drugs lipophilic organic compounds and only partially ionized at physiological pH?

Because we design drugs that are optimized for oral absorption. These properties allow the drug to be absorbed efficiently.

9

Why are lipophilic drugs poorly excreted by the kidney and liver?

-Binding to plasma proteins makes them unavailable for glomerular filtration in the kidneys
-Reabsorption at renal tubules and biliary epithelium (not excreted)
-They partition into lipid-rich tissues (e.g. adipose)

10

The purpose of metabolism in relation to drug excretion is to:

Increase polarity, ionization, and water solubility of drugs so that they can be excreted.

11

Metabolism limits the action of drugs in the body because of

Deactivation: Metabolites can have less pharmacological activity

12

Prodrugs

Drugs that have more active or toxic metabolites. The form given is not active; the drug relies on metabolism to activate it. This is aka bioactivation.

13

Bioactivation

Metabolism that activates a prodrug, making metabolites that are more active or toxic.

14

The major sites for the metabolism of drugs

Liver, but the intestine also has significant metabolic capacity for some drugs

15

Metabolism by __ & __ contribute to the first pass effect, which contributes to the bioavailability of drugs

the liver and intestine

16

Bioavailability

The amount of administered drug that reaches systemic circulation in unchange for following administration by any route.
-IV= 100%
-Oral < 100%
-Other routes ≤ 100%

17

A drug administered orally is subject to metabolism by:

The intestine and liver

18

Once an orally administered drug goes through the first pass, the drug that is left in the systemic circulation is only subject to metabolism by

The liver

19

Drug metabolism can be broken down into

Phase I and Phase II Metabolism

20

Phase I metabolism

The creation or unmasking of small polar or reactive functional groups (such as -OH, -SH, -NH2) to create a more polar metabolites

21

Phase II Metabolism

The addition (conjugation) of large polar groups to small reactive functional groups. Goal is to make a more polar metabolite.

E.g. glucuronic acid, sulfate, glutahione, acetate

22

(T/F) drugs must undergo both phase I and phase II metabolism

False. Some drugs only go through one phase, while others go through both sequentially. Phase I groups can be used as attachment groups for groups of phase II.

23

Hydroxylation in Phase I of a benzene ring

Benzene to epoxide (via CYP, cytochrome P450)
Epoxide to alcohol (in the presence of water)

24

Glucurondation in Phase II metabolism

An alcohol (from phase I) can be converted to a glucuronide conjugate via the addition of UDP-GA (catalyzed by UDP-GT). The -OH is used as an attachment point.

25

The rate at which most drugs are metabolized is generally determined by

Phase I metabolism

26

The most important enzyme group in phase I metabolism

Cytochrome P450s

27

Cytochrome P450 (CYP)

-Refers to a gene superfamily
-57 individual genes
-Multiple physiological roles (make essential steroids, vitamin metabolism, etc.)
-Families 1, 2, and 3 are most relevant to drug metabolism
-Most important contributors to Phase I metabolism

28

How to name Cytochrome P450 genes

CYP34A
-CYP= prefix
-3= Family
-A= Subfamily
4= isoform

29

Why does CYP have an extremely broad substrate range?

-Multiple isoforms
-Inherent low substrate specificity of individual isoforms

Gives incredibly diversity for drug metabolism

30

How does CYP affect pharmacokinetics?

Expression levels of CYP vary among individuals.