Chemical Methods for Improving PK

Question 1

the main parameters of optimizing pharmacokinetics are

Answer 1

aqueous solubility, chemical and metabolic stability, intestinal absorption

Question 2

structural bioisoteric qualities

Answer 2

size shape hbonding

Question 3

receptor interaction bioisoteric qualities

Answer 3

hbonding, electronic

Question 4

log P < 5 makes for

Answer 4

increased oral bioavailibility

Question 5

can you add or remove functional groups in the pharmacophore to improve hydrophylicity/hydrophobicity?

Answer 5

not so much, the pharmacophore is important!

Question 6

T/F: Adding or removing functional groups is a practical method for improving hydrophobicity?

Answer 6

F

Question 7

adding polar groups ______ the logP

Answer 7

decreases

Question 8

modifying _______ is a way of altering hydrophobicity

Answer 8

potential ionization sites

Question 9

pH of stomach

Answer 9

1-4

Question 10

pH of small intestine

Answer 10

7-8

Question 11

amide bonds are ____ to stomach pH

Answer 11

very susceptible

Question 12

use of ____ can help prevent amide hydrolysis

Answer 12

amide bond mimics

Question 13

name three ways to prevent degridation by peptidases and esterases

Answer 13

bond mimics, steric shields, bioisoteres

Question 14

steric shields use ___ to ______

Answer 14

a large steric group/ block enzyme from degrading

Question 15

problem of steric shields:

Answer 15

adding a large FG often changes PK properties

Question 16

to prevent degredation, we use ___ to make compound more stable and resist cleavage

Answer 16

electron donating

Question 17

_ in liver metabolizes many drugs

Answer 17

CYP450

Question 18

General metabolism: ______ then _______

Answer 18

oxidation/ conjugation

Question 19

CYP450 wants to make compounds ______

Answer 19

more water soluble

Question 20

CYP450 metabolizes at two main sites for aromatics:

Answer 20

methyl groups, para position to R group

Question 21

Solution to CYP450 metabolism:

Answer 21

use bioisoters

Question 22

species difference in metabolism is a major consideration in preclinical testing of prodrugs

Answer 22

true

Question 23

Type I prodrugs:

Answer 23

intracellular site of conversion

Question 24

Type IA prodrugs:

Answer 24

converted in therapeutic target tissue

Question 25

Type IB prodrugs:

Answer 25

converted in metabolic tissues

Question 26

Type II prodrugs

Answer 26

extracellular site of conversion

Question 27

Type IIA produrgs:

Answer 27

converted in GI fluid

Question 28

Type IIB prodrugs:

Answer 28

converted in systemic circulation

Question 29

metabolic tissues are:

Answer 29

liver and lungs

Question 30

liberation of prodrug:

Answer 30

active drug molecule is intact within overall structure of the prodrug

Question 31

bioactivation of prodrug:

Answer 31

must be converted into a new chemical structure - can be chemical or metabolic conversion

Question 32

ester prodrugs are commonly used to

Answer 32

enhance membrane permeability of easily ionizable carboxylic acid

Question 33

rate of cleavage is affected by ________ of ester

Answer 33

electronic effects

Question 34

_____ speed up cleaveage of ester prodrugs by making the ester ___

Answer 34

electron withdrawing groups/ unstable

Question 35

_____ speed down cleavage of ester prodrugs by making the ester ____

Answer 35

electron donating groups/ stable

Question 36

antibody drug conjugates:

Answer 36

prodrugs tied to antibodies –> target only certain cells

Question 37

trojan horse prodrugs:

Answer 37

allows a compound to get into cell and then convert to active form